4-aminoquinazoline derivatives

ABSTRACT

The compounds of the formula:     &lt;IMAGE&gt;  (I)  wherein R1, Y, A, R4, n, Z, CyB, R3, and m are defined in the specification.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of our copending applicationSer. No. 08/076,431 filed Jun. 14, 1993. now abandoned, which is acontinuation-in-part of our application Ser. No. 07/913,473 filed July15. 1992, which is now abandoned.

FIELD OF THE INVENTION

The present invention relates to novel 4-aminoquinazoline derivatives.More particularly, this invention relates to:

(i) 4-aminoquinazoline derivatives of the following formula: ##STR2##

wherein all of the symbols have the same meanings as describedhereinafter, and the pharmaceutically acceptable acid addition saltsthereof, the pharmaceutically acceptable salts thereof, and the hydratesthereof, which have inhibitory activity on cyclic guanosine3',5'-monophosphate phosphodiesterase, or additionally on thromboxane A2synthetase,

(ii) processes for the preparation thereof,

(iii) inhibitors of cyclic guanosine 3',5'-monophosphatephosphodiesterase, or additionally of thromboxane A2 synthetasecontaining them, and

(iv) methods of prevention and treatment of symptoms and diseases ofmammals, including humans, by administering an effective amount of thecompounds of the formula (I), the pharmaceutically acceptable acidaddition salts thereof, the pharmaceutically acceptable salts thereof,and the hydrates thereof, to the patient to be treated.

BACKGROUND OF THE INVENTION

Cyclic guanosine 3',5'-monophosphate (abbreviated as cGMP hereafter) wasfound in urine in rats by D. F. Ashman in 1963. Till now, it has beenknown that cGMP is distributed broadly in tissues of many animalsincluding human beings. cGMP is biosynthesized from guanosinetriphosphate (GTP) by the action of guanylate cyclase.

cGMP has been experimentally confirmed to have various physiologicalactivities. For example, cGMP induces the relaxation of heart muscle andof smooth muscle. Further, it is related to the formation of neuronalsynapses, and it acts as a trigger of cell proliferation and it inducesthe proliferation of lymphocyte.

cGMP is metabolized to physiologically inactive 5'-GMP by the action ofcGMP phosphodiesterase (abbreviated as cGMPoPDE hereafter).

Accordingly, the inhibition of the action of cGMP-PDE is considered tobe useful for the prevention and/or treatment of diseases induced byenhancement of the metabolism of cGMP, such as hypertension, heartfailure, myocardial infarction, angina, atherosclerosis, cardiac edema,renal insufficiency, nephrotic edema, hepatic edema, asthma, bronchitis,dementia, immunodeficiency, pulmonary hypertension.

On the other hand, thromboxane A2 (abbreviated as TXA₂ hereafter) wasfound as a constituent of the arachidonate cascade, in platelets by M.Hamberg in 1975. TXA₂ is biosynthesized from arachidonic acid releasedfrom cell membrane via prostaglandin G₂ and prostaglandin H₂, andrapidly metabolized to inactive thromboxane B₂. TXA₂ is known to induceplatelet aggregation and to contract smooth muscle, particularly bloodvessel muscle and bronchial muscle. TXA₂ synthetase was isolated andpurified from microsome in platelets.

Accordingly, the inhibition of TXA₂ synthetase decreases thebiosynthesis of TXA₂, and is useful for the prevention and/or treatmentof inflammation, hypertension, thrombosis, arteriosclerosis, cerebralapoplexy, asthma, myocardial infarction, cardiostenosis, cerebralinfarction, etc.

RELATED ARTS

Up to now, some compounds have been known as cGMP-PDE inhibitors, forexample, ##STR3##

Many compounds derived from the above lead compounds have been proposedand many patent applications relating to those have been filed. Forexample, as derivatives of Zaprinast, compounds wherein the1H-1,2,3-triazole skeleton is replaced by various other hetero cycles(see U.S. Pat. No. 5,047,404), those wherein the triazole is replaced bya benzene ring (see EP-371731), and those wherein the triazole iseliminated, i.e. those having only the pyrimidine skeleton (seeEP-395328), have been proposed. The above mentioned compounds alwayscontain an oxo group at the 4th position of the pyrimidine skeleton. Thecompounds having an amino group at the said position are described inU.S. Pat. No. 4,060,615. The specification discloses4-amino-6,7-dimethoxy-2-piperazinylquinazoline derivatives of thefollowing formula: ##STR4## wherein R^(d) is amino or hydrazino, R^(1d)is C3-8 cycloalkyl, C3-8 methylcycloalkyl or C4-8 cycloalkenyl, andtheir acid addition salts.

More recently, quinazoline derivatives having inhibitory activity oncGMP-PDE have been laid open (see WO 93/07124). In this specification,the quinazoline derivatives of the following formula is disclosed.##STR5## wherein ring A^(e) is, for example, benzene, cyclohexane; ringB^(e) is, for example, pyrimidine;

R^(1e), R^(2e), R^(3e) and R^(4e) are each, for example, hydrogen,halogen, lower alkyl optionally substituted by halogen, lower alkoxy,hydroxyalkyl, nitro, cyano, acylamino, optionally protected COOH,S(O)n^(e) --R^(7e) (n^(e) is 0,1,2, R^(7e) is lower alkyl), NR^(45e)R^(46e) (R^(45e) and R^(46e) are each, for example, hydrogen, loweralkyl);.

R^(5e) is, for example, optionally substituted heteroaryl (for example,pyridinyl, imidazolidinyl, qunazolidinyl);

R^(6e) is, for example, ##STR6##

(R^(17e) is, for example, hydrogen, lower alkyl, alkoxyalkyl,hydroxyalkyl;

Y^(e) is, for example, (CH₂)q^(e) (q^(e) is 0 to 8); R^(18e) is, forexample, hydrogen, hydroxy, optionally substituted heteroaryl,optionally substituted cycloalkyl), ##STR7##

(R^(19e) is, for example, hydrogen, lower alkyl; R^(20e), R²¹ e andR^(22e) are each, for example, hydrogen, halogen, nitro, low alkyl,alkoxy; r^(e) is 0 to 8);

Furthermore, some TXA₂ synthetase inhibitors have been known, forexample, ##STR8##

Many derivatives containing an imidazole or pyridine ring as the basicskeleton have been proposed. However, there appears to be no TXA₂synthetase inhibitor having both the said ring and quinazoline ring.

Each of the foregoing documents are herein incorporated, in theirentirety, by reference.

PURPOSE OF THE INVENTION

Energetic investigation has been carried out in order to discovercompounds having inhibitory activities on cGMP-PDE or additionally TXA₂synthetase, and as a result, the present inventors have found thecompounds of the present invention.

SUMMARY OF THE INVENTION

The present invention relates to:

(i) quinazoline derivatives of the formula: ##STR9## wherein R¹ ishydrogen or C1-4 alkyl;

Y is single bond or C1-6 alkylene;

A is

(i) --CyA--(R²)l,

(ii) --O--R⁰ or --S(O)p--R⁰

in which R⁰ is R^(0A) or ROB;

R^(0A) is --CyA--(R²)l;

R^(OB) is hydrogen or C1-4 alkyl; p is 0-2;

CyA is

(1) 3-7 membered, saturated or unsaturated, monocyclic carbocyclic ring,

(2) 7-membered, unsaturated or partially saturated, monocyclic heteroring containing as hetero atoms, one nitrogen atom, one nitrogen and oneoxygen atoms, two nitrogen and one oxygen atoms, or one nitrogen and twooxygen atoms,

(3) 6-membered, unsaturated or partially saturated, monocyclic heteroring containing as hetero atoms, one nitrogen and one oxygen atoms, twonitrogen and one oxygen atoms, or one nitrogen and two oxygen atoms,

(4) 6-membered, unsaturated or partially saturated, monocyclic heteroring containing as hetero atoms, one nitrogen atom,

(5) 4- or 5-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, one nitrogen atom, one nitrogenand one oxygen atoms, two nitrogen and one oxygen atoms, or one nitrogenand two oxygen atoms,

(6) 4-7 membered, unsaturated or partially saturated, monocyclic heteroring containing as hetero atoms, one or two sulfur atoms or

(7) 4-7 membered, unsaturated or partially or fully saturated,monocyclic hetero ring containing as hetero atoms, one or two oxygenatoms;

R² is R^(2A) or R^(2B) ;

R^(2A) is (1)--NRGAR^(7A), in which R^(6A) and R^(7A) independently arehydrogen or C1-4 alkyl (with the proviso that R^(6A) and R^(7A) are nothydrogen at same time), (2) -SO2NRGR⁷, in which R⁶ and R⁷ independentlyare hydrogen or C1-4 alkyl, (3) trifluoromethyl or (4) trifluoromethoxy;

R^(2B) is (1) hydrogen, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4)--COOR⁵, inwhich R⁵ is hydrogen or C1-4 alkyl, (5) halogen, (6) nitro or (7)--NRGBR^(7B), in which R^(6B) and R^(7B) are hydrogen;

Z is Z^(A) or Z^(B) ;

Z^(A) is methylene, ethylene (CH₂ CH₂), vinylene (CH═CH) or ethynylene(C.tbd.C);

Z^(B) is single bond;

CyB is

(1) 7-membered, unsaturated or partially saturated, monocyclic heteroring containing as hetero atoms, one, two or three nitrogen atoms,

(2) 6-membered, unsaturated or partially saturated, monocyclic heteroring containing as hetero atoms, two or three nitrogen atoms,

(3) 6-membered, unsaturated or partially saturated, monocyclic heteroring containing as hetero atoms, one nitrogen atom,

(4) 4- or 5-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, one, two or three nitrogenatoms, or

(5) 4-7 membered, unsaturated or partially saturated, monocyclic heteroring containing as hetero atoms, one or two oxygen atoms, or one or twosulfur atoms;

R3 is hydrogen, C1-4 alkyl, C1-4 alkoxy, halogen or trifluoromethyl;

R⁴ is R^(4A) or R^(4B) ;

R^(4A) is (1) --NHSO₂ R¹¹, in which R¹¹ is C1-4 alkyl, (2) SO₂ NR⁹ R¹⁰,in which R⁹ is hydrogen, C1-4 alkyl or phenyl(C1-4 alkyl) and R¹⁰ ishydrogen or C1-4 alkyl, (3) --OCOR¹¹, in which R¹¹ is as hereinbeforedefined, (4) hydroxy, (5) --SO₂ N═CHNR¹² R¹³ in which R¹² is hydrogen orC1-4 alkyl and R¹³ is C1-4 alkyl, (6) --CONR⁴ R¹⁵ in which R¹⁴ ishydrogen or C1-4 alkyl and R¹⁵ is C1-4 alkyl or phenyl(C1-4 alkyl), (7)ethynyl, (8) tri(C1-4 alkyl)silylethynyl or (9) acetyl;

R^(4B) is (1) hydrogen, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4)-COOR⁸, inwhich R8 is hydrogen or C1-4 alkyl, (5) --NR⁹ R¹⁰, in which R⁹ and R¹⁰are as hereinbefore defined, (6) --NHCOR¹¹, in which R¹¹ is ashereinbefore defined, (7) halogen, (8) trifluoromethyl, (9) nitro, (10)cyano, (11) C1-4 alkylthio, (12) C1-4 alkylsulfinyl, (13) C1-4alkylsulfonyl, (14) hydroxymethyl, and l, m and n independently are 1 or2; with the proviso that

(1) the group of the formula: --CyA--(R²)_(l) does not represent acyclopentyl and trifluoromethylphenyl group when Y is a single bond,that

(2) a CyB ring should not bond to Z through a nitrogen atom in the CyBring when Z is vinylene or ethynylene, that

(3) a CyB ring should not be pyridine or thiophene when CyA is a ring ofCyA--(7), that

(4) Y is not a single bond, when A is (ii) --O--RO or --S(O)p-R⁰ andthat

(5) A should not be --CyA--(R² B)l and --OR^(0B), when Z is Z^(B) and R⁴is R⁴ B; or pharmaceutically acceptable acid addition salts thereof,pharmaceutically acceptable salts thereof, or hydrates thereof,

(ii) process for the preparation thereof,

(iii) cGMP-PDE inhibitors, or additionally TXA₂ synthetase inhibitors,containing them as active ingredient, and

(iv) methods of prevention and treatment of mammals, including humans,by administering an effective amount of the compounds of the formula(I), the pharmaceutically acceptable acid addition salts thereof, thepharmaceutically acceptable salts thereof, and the hydrates thereof, tothe patient to be treated.

This present invention can be classified in three groups of the formulaindicated as follows;

(1) A compound of the formula [I-(A)]; ##STR10## (wherein Z^(A) ismethylene, ethylene, vinylene or ethynylene; and the other symbols havethe same meanings as hereinbefore defined)

(2) A compound of the formula [I-(B)]; ##STR11## (wherein Z^(B) issingle bond; R^(4A) is --NHSO₂ R¹¹, SO₂ NR⁹ R¹⁰, --OCOR¹¹, hydroxy,--SO₂ N═CHNR¹² R¹³, --CONR¹⁴ R¹⁵, ethynyl, tri(C1-4 alkyl)silylethynylor acetyl; and the other symbols have the same meanings as hereinbeforedefined)

(3) A compound of the formula [I-(C)]; ##STR12## (wherein Z^(B) issingle bond; A^(C) is --CyA--(R² A)l, --O--R^(0A) or --S(O)p--R⁰ ;R^(0A) is --CyA--(R²)l; R⁰ is hydrogen, C1-4 alkyl or--CyA--(R²)l; p is0-2; R^(2A) is --NRGAR^(7A) (with the proviso that R^(6A) and R^(7A) arenot hydrogen at same time), --SO₂ NRGR⁷, trifluoromethyl ortrifluoromethoxy; R^(4B) is hydrogen, C1-4 alkyl, C1-4 alkoxy, --COOR⁸,--NR⁹ R¹⁰, --NHCOR¹¹, halogen, trifluoromethyl, nitro, cyano, C1-4alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, hydroxymethyl; andthe other symbols have the same meanings as hereinbefore defined) orpharmaceutically acceptable acid addition salts thereof,pharmaceutically acceptable salts thereof, or hydrates thereof.

COMPARISON

There is no description of the compounds of the formula (I) of thepresent invention in those of the formulae (D) and (E) mentioned above.In detailed description, the compounds of the formula (I), of thepresent

invention have --N--Y--A (i.e., Y is single bond or alkyl, A is--CyA--(R²)L, --O--R⁰ or --S(O)p--R⁰) group at the 4th position of aquinazoline skeleton. On the other hand, the compounds of the formula(D) in the related arts have merely an amino or hydrazino group.

The compounds of the formula (I) differ from those of formula (E) at thefollowing points.

(1) Z^(A) in the formula [I-(A)] dose not represent a single bond (thatis, CyB is bonded to the quinazoline skeleton through a carbon chain.),but in the formula (E), R^(5e) (heteroaryl) is directly bonded to theskeleton ring B^(e),

(2) R^(4A) in the formula [I-(B)] represents definite groups, i.e.,sulfonylamino, aminosulfonyl, acyloxy, hydroxy, --SO₂ N═CHNR¹² R¹³,aminocarbonyl, ethynyl, tri(C1-4alkyl)silylethynyl, acetyl group, butR^(1e) to R^(4e) in the formula (E) do not represent them at all,

(3) when A^(C) in the formula [I-(C)] represents --CyA(R² A)l, R^(2A),the substituents of CyA, represents alkylamino, aminosulfonyl,trifluoromethane or trifluoromethoxy. However, in the formula(E),substituents R^(20e) to R^(22e), and substituents "substitutedheteroaryl" or "substituted cycloalkyl", do not represent those ofR^(2A),

(4) A^(C) in the formula [I-(C)] represents oxygen-containing group(i.e., 0--CyA-(R²)l), but R^(6e) in the formula (E) dose not representthe group of O-cyclic ring, and

(5) A^(C) in the formula [I-(C)] represents sulfur-containing group(i.e., S(O)p--R⁰), but R^(6e) in the formula (E) does not represent sucha group.

Accordingly, the compounds of the present invention are quite novel.Furthermore, the fact that compounds of the present invention haveinhibitory activity on cGMP-PDE or additionally TXA₂ synthetase, is notsuggested from pharmaceutical use disclosed in any related artsmentioned above. Accordingly, the compounds of the present invention areuseful for the prevention and/or treatment of diseases induced by onlyenhancement of the metabolism of cGMP, or the increase of TXA₂, orinduced by both factors.

DETAILED DESCRIPTION OF THE INVENTION

In the formula (I), the C1-4 alkyl group represented by R⁰, R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵, mean methyl,ethyl, propyl, butyl and the isomers thereof.

In the formula (I), the C1-4 alkoxy group represented by R², R³ and R⁴mean methoxy, ethoxy, propoxy, butoxy and isomers thereof.

In the formula (I), the halogen atom represented by R², R³ and R⁴ meanfluorine, chlorine, bromine and iodine.

In the formula (I), the C1-6 alkylene group represented by Y meansmethylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene and isomers thereof.

In the formula (I), examples of 3-7 membered, saturated or unsaturated,monocyclic carbocyclic ring, represented by CyA--(1), arecyclobutadiene, cyclopentadiene, benzene, cycloheptatriene ring, andpartially or fully saturated rings thereof, for example, cyclobutane,cyclopentane, cyclohexane, cycloheptane ring, and cyclopropane ring.

Examples of 7-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, one nitrogen atom, one nitrogenand one oxygen atoms, two nitrogen and one oxygen atoms, or one nitrogenand two oxygen atoms, represented by CyA--(2), are azepine, oxazepine,and partially saturated rings thereof.

Examples of 6-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, one nitrogen and one oxygenatoms, two nitrogen and one oxygen atoms, or one nitrogen and two oxygenatoms, represented by CyA--(3), are oxazine, oxadiazine, and partiallysaturated rings thereof.

Examples of 6-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, one nitrogen atom, representedby CyA--(4) and CyB-(3), are pyridine, dihydropyridine, andtetrahydropyridine.

Examples of 4- or 5-membered, unsaturated or partially saturated,monocyclic hetero ring containing as hetero atoms, one nitrogen atom,one nitrogen and one oxygen atoms, two nitrogen and one oxygen atoms, orone nitrogen and two oxygen atoms, represented by CyA--(5), are pyrrole,azetine, oxazole, isoxazole, furazan, and partially saturated ringsthereof.

Examples of 4-7 membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, one or two sulfur atoms,represented by CyA--(6), are thiophene, thiain, dithiain, and partiallysaturated rings thereof.

Examples of 4-7 membered, unsaturated or partially or fully saturated,monocyclic hetero ring containing as hetero atom one oxygen atomrepresented by CyA--(7), are furan, pyran, dioxin and partially or fullysaturated rings thereof.

In the formula (I), examples of 7-membered, unsaturated or partiallysaturated, monocyclic hetero ring containing as hetero atoms, one, twoor three nitrogen atoms, represented by CyB-(1 ), are azepine,diazepine, triazepine, and partially saturated rings thereof.

Examples of 6-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, two or three nitrogen atoms,represented by CyB-(2) are pyridazine, pyrimidine, pyrazine, triazine,and partially saturated rings thereof.

Examples of 4- or 5-membered, unsaturated or partially saturated,monocyclic hetero ring containing as hetero atoms, one, two or threenitrogen atoms, represented by CyB-(4), are pyrrole, imidazole,pyrazole, triazole, azetine, and partially saturated rings thereof,

Examples of 4-7 membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, one or two oxygen atoms, or oneor two sulfur atoms represented by CyB-(5), are thiophene, furan,thiain, pyran, dithiain, dioxin, dioxole, and partially saturated ringsthereof.

Examples of representative compounds of the present invention are listedas follows:

    __________________________________________________________________________    1   4-(4-(N,N-dimethylamino)phenylmethyl)amino-2-(3-pyridyl)-quinazoline,         9                                                                         2   4-(4-sulfamoylphenylmethyl)amino-2-(3-pyridyl)quinazoline,                3   4-(3-trifluoromethylphenylmethyl)amino-2-(3-pyridyl)quinazoline,          4   4-(3-trifluoromethoxyphenylmethyl)amino-2-(3-pyridyl)quinazoline,         5   4-phenylmethylamino-6-methanesulfonylamino-2-(3-pyridyl)quinazoline,      6   4-phenylmethylamino-6-dimethylaminosulfonyl-2-(3-pyridyl)quinazoline,         2                                                                         7   4-phenylmethylamino-6-sulfamoyl-2-(3-pyridyl)quinazoline,                 8   4-phenylmethylamino-6-acetoxy-2-(3-pyridyl)quinazoline,                   9   4-phenylmethylamino-6-hydroxy-2-(3-pyridyl)quinazoline,                   10  4-phenylmethylamino-6-(N,N-dimethylaminocarbonyl)-2-(3-pyridyl)quinazo        line,                                                                     11  4-phenylmethylamino-6-ethynyl-2-(3-pyridyl)quinazoline,                   12  4-phenylmethylamino-6-trimethylsilylethynyl-2-(3-pyridyl)quinazoline,         .                                                                         13  4-phenylmethylamino-6-acetyl-2-(3-pyridyl)quinazoline,                    14  4-phenylmethylamino-6-methanesulfonylamino-2-(4-pyridyl)quinazoline,      15  4-phenylmethylamino-6-dimethylaminosulfonyl-2-(4-pyridyl)quinazoline,     16  4-phenylmethylamino-6-sulfamoyl-2-(4-pyridyl)quinazoline,                 17  4-phenylmethylamino-6-hydroxy-2-(4-pyridyl)quinazoline,                   18  4-phenylmethylamino-6-(N,N-dimethylaminocarbonyl)-2-(3-pyridyl)quinazo        line,                                                                     19  4-phenylmethylamino-6-ethynyl-2-(4-pyridyl)quinazoline,                   20  4-phenylmethylamino-6-trimethylsilylethynyl-2-(4-pyridyl)quinazoline,     21  4-phenylmethylamino-6-acetyl-2-(4-pyridyl)quinazoline,                    22  4-phenylmethylamino-6-methanesulfonylamino-2-(1-imidazolyl)quinazoline        ,                                                                         23  4-phenylmethylamino-6-dimethylaminosulfonyl-2-(1-imidazolyl)quinazolin        e,                                                                        24  4-phenylmethylamino-6-sulfamoyl-2-(1-imidazolyl)quinazoline,              25  4-phenylmethylamino-6-hydroxy-2-(1-imidazolyl)quinazoline,                26  4-phenylmethylamino-6-(N,N-dimethylaminocarbonyl)-2-(1-imidazolyl)quin        azoline,                                                                  27  4-phenylmethylamino-6-ethynyl-2-(1-imidazolyl)quinazoline,                28  4-phenylmethylamino-6-trimethylsilylethynyl-2-(1-imidazolyl)quinazolin        e,                                                                        29  4-phenylmethylamino-6-acetyl-2-(1-imidazolyl)quinazoline,                 30  4-phenylmethylamino-2-(2-(3-pyridyl)ethyl)quinazoline,                    31  4-phenylmethylamino-2-(2-(3-pyridyl)vinyl)quinazoline,                    32  4-phenylmethylamino-2-((1-imidazolyl)methyl)quinazoline,                  33  6-methanesulfonylamino-4-(4-tetrahydropyranylmethyl)amino-2-(1-imidazo        lyl)quinazoline,                                                          34  6-dimethylaminosulfonylamino-4-(4-tetrahydropyranylmethyl)amino-2-(1-i        midazolyl)quinazoline,                                                    35  6-sulfamoyl-4-(4-tetrahydropyranylmethyl)amino-2-(1-imidazolyl)quinazo        line,                                                                     36  6-hydroxy-4-(4-tetrahydropyranylmethyl)amino-2-(1-imidazolyl)quinazoli        ne,                                                                       37  6-(N,N-dimethylaminocarbonyl)-4-(4-tetrahydropyranylmethyl)amino-2-(1-        imidazolyl)quinazoline,                                                   38  6-ethynyl-4-(4-tetrahydropyranylmethyl)amino-2-(1-imidazolyl)quinazoli        ne,                                                                       39  6-trimethylsilylethynyl-4-(4-tetrahydropyranylmethyl)amino-2-(1-imidaz        olyl)quinazoline,                                                         40  6-acetyl-4-(4-tetrahydropyranylmethyl)amino-2-(1-imidazolyl)quinazolin        e,                                                                        41  6-methanesulfonylamino-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazo        line,                                                                     42  6-dimethylaminosulfonyl-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinaz        oline,                                                                    43  6-sulfamoyl-4-(2-methoxyethyl)amino-2-(imidazolyl)quinazoline,            44  6-hydroxy-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazoline,            45  6-(N,N-dimethylaminocarbonyl)-4-(2-methoxyethyl)amino-2-(1-imidazolyl)        quinazoline,                                                              46  6-ethynyl-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazoline,            47  6-trimethylsilylethynyl-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinaz        oline,                                                                    48  6-acetyl-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazoline,             49  6-methanesulfonylamino-4-(2-dimethylaminoethyl)amino-2-(1-imidazolyl)q        uinazoline,                                                               50  6-dimethylaminosulfonyl-4-(2-dimethylaminoethyl)amino-2-(1-imidazolyl)        quinazoline,                                                              51  6-sulfonyl-4-(2-dimethylaminoethyl)amino-2-(1-imidazolyl)quinazoline,     52  6-hydroxy-4-(2-dimethylaminoethyl)amino-2-(1-imidazolyl)quinazoline,      53  6-(N,N-dimethylaminocarbonyl)-4-(2-dimethylaminoethyl)amino-2-(1-imida        zolyl)quinazoline,                                                        54  6-ethynyl-4-(2-dimethylaminoethyl)amino-2-(1-imidazolyl)quinazoline,      55  6-trimethylsilylethynyl-4-(2-dimethylaminoethyl)amino-2-(1-imidazolyl)        quinazoline,                                                              56  6-acetyl-4-(2-dimethylaminoethyl)amino-2-(1-imidazolyl)quinazoline,       57  6-methanesulfonylamino-4-(2-phenoxyethyl)amino-2-(1-imidazolyl)quinazo        line,                                                                     58  6-dimethylaminosulfonyl-4-(2-phenoxyethyl)amino-2-(1-imidazolyl)quinaz        oline,                                                                    59  6-sulfamoyl-4-(2-phenoxyethyl)amino-2-(1-imidazolyl)quinazoline,          60  6-hydroxy-4-(2-phenoxyethyl)amino-2-(1-imidazolyl)quinazoline,            61  6-(N,N-dimethylaminocarbonyl)-4-(2-phenoxyethyl)amino-2-(1-imidazolyl)        quinazoline,                                                              62  6-ethynyl-4-(2-phenoxyethyl)amino-2-(1-imidazolyl)quinazoline,            63  6-trimethylsilylethynyl-4-(2-phenoxyethyl)amino-2-(1-imidazolyl)quinaz        oline,                                                                    64  7-acetyl-4-(2-phenoxyethyl)amino-2-(1-imidazolyl)quinazoline,             65  6-ethynyl-4-(2-methoxyethyl)amino-2-(2-azepinyl)quinazoline,              66  6-ethynyl-4-(2-methoxyethyl)amino-2-(1,5-diazepin-2-yl)quinazoline,       67  6-ethynyl-4-(2-methoxyethyl)amino-2-(2-pyrimidinyl)quinazoline,           68  6-ethynyl-4-(2-methoxyethyl)amino-2-(2-triazinyl)quinazoline,             69  6-ethynyl-4-(2-methoxyethyl)amino-2-(2-pyridyl)quinazoline,               70  6-ethynyl-4-(2-methoxyethyl)amino-2-(4-pyridyl)quinazoline,               71  6-ethynyl-4-(2-methoxyethyl)amino-2-(2-(3-pyridyl)ethyl)quinazoline,      72  6-ethynyl-4-(2-methoxyethyl)amino-2-(2-(3-pyridyl)vinyl)quinazoline,      73  6-ethynyl-4-(2-methoxyethyl)amino-2-(2-pyrrolyl)quinazoline,              74  6-ethynyl-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazoline,            75  6-ethynyl-4-(2-methoxyethyl)amino-2-((1-imidazolyl)methyl)quinazoline,    76  6-ethynyl-4-(2-methoxyethyl)amino-2-(2-methyl-1-imidazolyl)quinazoline        ,                                                                         77  6-ethynyl-4-(2-methoxyethyl)amino-2-(1-triazolyl)quinazoline,             78  6-ethynyl-4-(2-methoxyethyl)amino-2-(2-thienyl)quinazoline,               79  6-ethynyl-4-(2-methoxyethyl)amino-2-(2-furyl)quinazoline,                 80  6-ethynyl-4-((2-azepinylmethyl)methyl)amino-2-(3-pyridyl)quinazoline,     81  6-ethynyl-4-((3-pyridylmethyl)methyl)amino-2-(3-pyridyl)quinazoline,      82  6-ethynyl-4-((1-methyl-2-pyrrolyl)methyl)amino-2-(3-pyridyl)quinazolin        e,                                                                        83  6-ethynyl-4-((3-isoxazolyl)methyl)amino-2-(3-pyridyl)quinazoline,         84  6-ethynyl-4-((2-thienylmethyl)methyl)amino-2-(3-pyridyl)quinazoline,      85  6-ethynyl-4-(3-pyridylmethyl)amino-2-(3-pyridyl)quinazoline,              86  4-(2-methylthioethyl)amino-2-(2-azepinyl)quinazoline,                     87  4-(2-methylthioethyl)amino-2-(1,5-diazepin-2-yl)quinazoline,              88  4-(2-methylthioethyl)amino-2-(2-pyrimidinyl)quinazoline,                  89  4-(2-methylthioethyl)amino-2-(2-triazinyl)quinazoline,                    90  4-(2-methylthioethyl)amino-2-(2-pyridyl)quinazoline,                      91  4-(2-methylthioethyl)amino-2-(4-pyridyl)quinazoline,                      92  4-(2-methylthioethyl)amino-2-(2-(3-pyridyl)ethyl)quinazoline,             93  4-(2-methylthioethyl)amino-2-(2-(3-pyridyl)vinyl)quinazoline,             94  4-(2-methylthioethyl)amino-2-(2-pyrrolyl)quinazoline,                     95  4-(2-methylthioethyl)amino-2-(1-imidazolyl)quinazoline,                   96  4-(2-methylthioethyl)amino-2-((1-imidazolyl)quinazoline,                  97  4-(2-methylthioethyl)amino-2-(2-methyl-1-imidazolyl)quinazoline,          98  4-(2-methylthioethyl)amino-2-(1-triazolyl)quinazoline,                    99  4-(2-methylthioethyl)-2-(2-thienyl)quinazoline,                           100 4-(2-methylthioethyl)amino-2-(2-furyl)quinazoline,                        101 4-(2-methylsulfinylethyl)amino-2-(2-azepinyl)quinazoline,                 102 4-(2-methylsulfinylethyl)amino-2-(1,5-diazepin-2-yl)quinazoline,          103 4-(2-methylsulfinylethyl)amino-2-(2-pyrimidinyl)quinazoline,              104 4-(2-methylsulfinylethyl)amino-2-(2-triazinyl)quinazoline,                105 4-(2-methylsulfinylethyl)amino-2-(2-pyridyl)quinazoline,                  106 4-(2-methylsulfinylethyl)amino-2-(4-pyridyl)quinazoline,                  107 4-(2-methylsulfinylethyl)amino-2-(2-(3-pyridyl)ethyl)quinazoline,         108 4-(2-methylsulfinylethyl)amino-2-(2-(3-pyridyl)vinyl)quinazoline,         109 4-(2-methylsulfinylethyl)amino-2-(2-pyrrolyl)quinazoline,                 110 4-(2-methylsulfinylethyl)amino-2-(1-imidazolyl)quinazoline,               111 4-(2-methylsulfinylethyl)amino-2-((1-imidazolyl)methyl)quinazoline,       112 4-(2-methylsulfinylethyl)amino-2-(2-methyl-1-imidazolyl)quinazoline,      113 4-(2-methylsulfinylethyl)amino-2-(1-triazolyl)quinazoline,                114 4-(2-methylsulfinylethyl)amino-2-(2-thienyl)quinazoline,                  115 4-(2-methylsulfinylethyl)amino-2-(2-furyl)quinazoline,                    116 4-(2-methylsulfonylethyl)amino-2-(2-azepinyl)quinazoline,                 117 4-(2-methylsulfonylethyl)amino-2-(1,5-diazepin-2-yl)quinazoline,          118 4-(2-methylsulfonylethyl)amino-2-(2-pyrimidinyl)quinazoline,              119 4-(2-methylsulfonylethyl)amino-2-(2-triazinyl)quinazoline,                120 4-(2-methylsulfonylethyl)amino-2-(2-pyridyl)quinazoline,                  121 4-(2-methylsulfonylethyl)amino-2-(4-pyridyl)quinazoline,                  122 4-(2-methylsulfonylethyl)amino-2-(2-(3-pyridyl)quinazoline,               123 4-(2-methylsulfonylethyl)amino-2-(2-(3-pyridyl)quinazoline,               124 4-(2-methylsulfonylethyl)amino-2-(2-pyrrolyl)quinazoline,                 125 4-(2-methylsulfonylethyl)amino-2-(1-imidazolyl)quinazoline,               126 4-(2-methylsulfonylethyl)amino-2-((1-imidazolyl)methyl)quinazoline,       127 4-(2-methylsulfonylethyl)amino-2-(2-methyl-1-imidazolyl)quinazoline,      128 4-(2-methylsulfonylethyl)amino-2-(1-triazolyl)quinazoline,                129 4-(2-methylsulfonylethyl)amino-2-(2-thienyl)quinazoline,                  130 4-(2-methylsulfonylethyl)amino-2-(2-furyl)quinazoline,                    __________________________________________________________________________

and further those described in Examples below are also representativecompounds of the present invention.

Salts and Acid Addition Salts

The compounds of the formula (I), if desired, may be converted into acidaddition salts by known methods. Preferably, acid addition salts arenon-toxic and water-soluble. The suitable acid addition salts are, forexample, salts of an inorganic acid such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid,nitric acid, or an organic acid such as acetic acid, lactic acid,tartaric acid, benzoic acid, citric acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,isethionic acid, glucuronic acid and gluconic acid.

The compounds of the formula (I), if desired, may be converted intosalts by known methods. Preferable, salts are non-toxic salts andwater-soluble. The suitable salts are salts of alkaline metal (sodium,potassium etc.), salts of alkaline earth metal (calcium, magnesiumetc.), ammonium salts, salts of pharmaceutically acceptable organicamine (tetramethylammonium, triethylamine, methylamine, dimethylamine,cyclopentylamine, phenylmethylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine,lysine, arginine, N-methyl-D-glucamine etc.).

Throughout the specification including claims, it may be easilyunderstood by those skilled in the art, that the alkyl, alkoxy, groupsinclude straight-chained and also branched-chained ones. Accordingly,all isomers produced by the difference in stereo configuration, such asasymmetric carbons are included in the present invention.

Preparations

According to the present invention, of the compounds of the presentinvention, the compounds of the formula: ##STR13## wherein R⁴¹ is (1)hydrogen, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) --COOR⁸, (5) --NR⁹¹ R¹⁰¹,in which R⁹¹ is hydrogen, C1-4 alkyl or phenyl(C1-4 alkyl) and R¹⁰¹ ishydrogen or C1-4 alkyl, provided that both R⁹¹ and R¹⁰¹ are nothydrogen, (6) SO₂ NR⁹ R¹⁰, in which R⁹ and R¹⁰ are as hereinbeforedefined, (7) halogen, (8)trifluoromethyl, (9) nitro, (10)cyano, (11)C1-4alkylthio, (12) tri(C1-4 alkyl)silylethynyl, (13) --SO₂ N═CHNR¹² R¹³, inwhich R¹² and R¹³ are the same meaning as hereinbefore defined, or (14)--CONR¹⁴ R¹⁵, in which R¹⁴ and R¹⁵ are the same meaning as hereinbeforedefined, CyB¹ is as hereinbefore defined for CyB, provided that a carbonatom in the ring should bond to Z, and the other symbols are ashereinbefore defined; and the compounds of the formula: ##STR14##wherein Z¹ is single bond or methylene, CyB² is as hereinbefore definedfor CyB, provided that a nitrogen atom in the ring should bond to Z¹,and the other symbols are as hereinbefore defined; may be prepared byusing a series of reactions depicted in Scheme A and B, respectively,wherein R⁵⁰ is C1-4 alkyl and the other symbols are as hereinbeforedefined. ##STR15##

Each reaction in Scheme A and B may be carried out by methods known perse, under conditions described therein.

For example, the compounds of the formula (IA) may be prepared fromthose of the formula (V) by the reaction with an amine of the formula(IX) in a proper organic solvent such as a lower alkanol (e.g. ethanol)or tetrahydrofuran, or a mixture thereof, at a temperature from ambientto reflux, for several hours to several days, if necessary in thepresence of a base such as triethylamine.

Further, the compounds of the formula (IB) may be prepared from those ofthe formula (XII) by the reaction with a cyclic amine of the formula(XVI) in phenol at a reflux temperature for several hours.

Furthermore, the compounds of the present invention, of the formula:##STR16## wherein the various symbols are as hereinbefore defined; maybe prepared from those of the formula: ##STR17## wherein the varioussymbols are as hereinbefore defined; by the methods describedhereinbefore for the conversion of the compounds of the formula (V) intothose of the formula (IA). The compounds of the formula (XVII) may beprepared by the methods similar to those described hereinbefore inScheme A.

On the other hand, the compounds of the formula (I) other than those ofthe formulae (IA), (lB) and (IC) may be prepared by the methods knownper se described below.

The compounds of the formula (I) wherein R⁴ is amino may be preparedfrom those wherein R⁴ is nitro, by the reduction with zinc etc. in aproper organic solvent.

The compounds of the formula (I) wherein R⁴ is hydroxy may be preparedfrom those wherein R⁴ is alkoxy such as methoxy, by the reaction withhydrogen bromide or tribromoboron.

The compounds of the formula (I) wherein R⁴ is--NHCOR¹¹, wherein R¹¹ isas hereinbefore defined, may be prepared from those wherein R⁴ is nitro,by the reaction with the corresponding organic acid such as acetic acidin the presence of zinc dust.

The compounds of the formula (I) wherein R⁴ is NHSO₂ R¹¹, wherein R¹¹ isas hereinbefore defined, may be prepared from those wherein R4 is aminoby the reaction with the corresponding alkylsulfonyl chloride such asmethanesulfonyl chloride.

The compounds of the formula (I) wherein R⁴ is --OCOR¹¹, wherein R¹¹ isas hereinbefore defined, may be prepared from those wherein R⁴ ishydroxy by the esterification with the corresponding organic acid suchas acetic acid.

The compounds of the formula (I) wherein R⁴ is C1-4 alkylsulfinyl orC1-4 alkylsulfonyl may be prepared from those wherein R⁴ is C1-4alkylthio by the oxidation by oxidating agent such as hydrogen peroxide.

The compounds of the formula (I) wherein R⁴ is hydroxymethyl may beprepared from those wherein R⁴ is alkyoxycarbonyl, by the reduction withreducing agent such as lithium borohydride, lithium aluminum hydrideetc.

The compounds of the formula (I) wherein R⁴ is ethynyl may be preparedfrom those wherein R⁴ is tri(C1-4 alkyl)silylethynyl, by the removalreaction of silyl group with tetrabutylammonium halide.

The compounds of the formula (I) wherein R⁴ is acetyl may be preparedfrom those wherein R⁴ is ethynyl, by the reaction with mercury sulfateand acetic acid in an acidic condition.

In each reaction in the present specification, products may be purifiedby conventional manner. For example, it may be carried out bydistillation at atmospheric or reduced pressure, high performance liquidchromatography, thin layer chromatography or column chromatography usingsilica gel or magnesium silicate, washing or recrystallization.Purification may be carried out after each reaction, or after a seriesof reactions.

The starting materials of the formulae (II), (VI) and (XIII), and eachreagents of the formulae (VII), (VIII), (IX), (XV), (XVI), (XVII) and(XVIII) used in the process for the preparation of the present inventionare known per se or may be easily prepared by known methods.

Effect

The compounds of the formula (I), pharmaceutically acceptable acidaddition salts thereof, pharmaceutically acceptable salts thereof, orhydrates thereof, of the present invention have an inhibitory effect oncGMPPDE, or additionally on TXA₂ synthetase, and are, therefore, usefulfor the prevention and/or treatment of not only diseases induced byenhancement of the metabolism of cGMP, such as hypertension, heartfailure, myocardial infarction, angina, atherosclerosis, cardiac edema,renal insufficiency, nephrotic edema, hepatic edema, asthma, bronchitis,dementia, immunodeficiency, pulmonary hypertension, but also diseasesinduced by enhancement of the synthesis of TXA₂ such as inflammation,thrombosis, cerebral apoplexy, asthma, cardiostenosis, cerebralinfarction etc, in mammals, especially in humans.

The inhibitory effect on cGMP-PDE and TXA₂ synthetase, of the compoundsof the present invention were confirmed by screening tests as describedbelow.

(1) Inhibitory effect on cGMP-PDE Method

PDE IC was isolated from human platelets according to standard methodspreviously described in Lugnier, C. et al., Biochem. Pharmacol. 35:1743, 1986 (incorporated in its entirety by reference). Typically,connective tissue and adventitia were removed and 1-2 units of plateletswere suspended in 10 volumes of buffer A (20 mM Tris-HCl, pH 7.5,containing 2 mM magnesium acetate, 1 mM dithiothreitol, and 5 mMNa2EDTA) using a Brinkman polytron. The proteinase inhibitors leupeptin,pepstatin A, and phenylmethyl-sulfonyl fluoride (PMSF) were alsoincluded in this buffer (final concentration of 100 nM each). Thehomogenate was centrifuged at 100,000g for 60 minutes. The supernatantwas then removed and filtered through four layers of cheesecloth. Thesupernatant was applied to a DWAE-Trisacryl M column. The column waswashed with several bed volumes of buffer B (20 mM Tris-HCl, pH 7.5,containing 2 mM magnesium acetate, 1 mM dithiothreitol, and proteinaseinhibitors) and eluted by two successive linear NaCl gradients(0.05-0.15M, 300 ml total; 0.15-0.40M, 200 ml total). Five milliliterfractions were collected and assayed for cyclic GMP PDE activity.

Phosphodiesterase activity was measured, as described by Thompson, etal., Adv. Cyclic Nucleotide Res. 10: 69, 1979 (incorporated in itsentirety by reference), in a reaction medium containing 40 mM Tris-HCl(pH 8.0), 5 mM MgCl2, and 1 mM dithiothreitol. The concentration ofsubstrate (³ H-cGMP) was 0.2 mM. Compounds of the present invention weredissolved in dimethyl sulfoxide (DMSO) at a final concentration of 2.5%.This concentration of DMSO inhibited enzyme activity by approximately10%. The IC₅₀ values (concentration that produced 50% inhibition ofsubstrate hydrolysis) for the compounds examined were determined fromconcentration-response curves in which concentrations typically rangedfrom 10⁻⁸ to 10⁻³ M for the less potent inhibitors (half-logincrements).

Result

                  TABLE 1                                                         ______________________________________                                        Inhibitory activity on cGMP-PDE                                               Compounds             Inhibitory activity                                     Example No.           IC.sub.50, (M)                                          ______________________________________                                        3(o)          (3HCl salt) 2.4 × 10.sup.-6                               6(b)          (2HCl salt) 3.0 × 10.sup.-7                               6(j)          (2HCl salt) 1.35 × 10.sup.-7                              7             (free base) 2.0 × 10.sup.-7                               18            (2HCl salt) 4.6 × 10.sup.-8                               18(b)         (2HCl salt) 5.3 × 10.sup.-10                              ______________________________________                                    

(2) Inhibitory effect on TXA₂ synthetase Method

Male Wistar rats were starved overnight. Five hundreds microliter ofheparinized (10 U/mL) whole blood was collected from abdominal aortausing polyethylene syringe (needle: 22 or 26G). The blood freshly drawnfrom animal was preincubated with 5 μL of test compound at 37° C. Fiveminutes later, 2.5 μL of 6 mM of Ca ionophore A23187 (finalconcentration of 30 μM) was added into tube, and incubation mixture wasfurther incubated for 15 min. The reaction was terminated bycentrifugation of tubes at 12,000 rpm for 2 min. TXB₂ content in thesupernatant was determined by EIA as follows.

One milliliter of 0.5M glycine-HCl buffer (pH 3.2) was added to 100 μLof sample. The samples were mixed well and centrifuged at 1,700 G for 10min at 4° C. The extracted supernatant was applied to a SEP-PAK(registered Trade Mark) C₁₈ cartridge (Waters Assoc.). After washingwith 10 mL of distilled water followed by 10 mL each of 15% ethanol andpetroleum ether, the sample was eluted with 3 mL of ethyl acetate. Theethyl acetate fraction was evaporated to dryness under gentle N₂ streamand the residue was dissolved in EIA buffer (final volume of 1 mL)following the addition of 300 μL of 0.01M NaHCO₃ -NaOH buffer (pH 10.0).EIA for TXB₂ was carried out according to a legend attached to the kit(Chyman Chemical Co., Inc.). Overall recovery of TXB² in this extractionprocedure was 90%. The IC₅₀ values (concentration that produced 50%inhibition of TXB₂ synthesis) for the compounds examined were determinedfrom concentration-response curves.

Result

                  TABLE 2                                                         ______________________________________                                        Inhibitory activity on TXA.sub.2 synthetase                                   Compounds                 Inhibitory activity                                 Example No.               IC.sub.50, (M)                                      ______________________________________                                        18            (2HCl salt) 2.4 × 10.sup.-6                               ______________________________________                                    

On the other hand, it was confirmed that the acute toxicity of thecompound of the present invention is very weak. Therefore, the compoundsof the present invention may be considered to be sufficiently safe andsuitable for pharmaceutical use.

Application for Pharmaceuticals

For the purpose above described, the compounds, of the formula (I), ofthe present invention, pharmaceutically acceptable acid addition saltsthereof and hydrates thereof may be normally administered systemicallyor partially, usually by oral or parenteral administration.

The doses to be administered are determined depending upon age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person are generally between 1 mg and 1000 mg, byoral administration, up to several times per day, and between 1 mg and100 mg, by parenteral administration up to several times per day, orcontinuous administration between 1 and 24 hrs. per day intravenously.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

Administration of the compounds of the present invention, may be assolid compositions, liquid compositions or other compositions for oraladministration, as injections, liniments or suppositories etc. forparenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, dispersible powders, and granules. Capsules includehard capsules and soft capsules.

In such compositions, one or more of the active compound(s) is or are,admixed with at least one inert diluent (such as lactose, mannitol,glucose, hydroxypropyl cellulose, micro crystalline cellulose, starch,polyvinylpyrrolidone, magnesium metasilicate aluminate etc.) Thecompositions may also comprise, as is normal practice, additionalsubstances other than inert diluents: e.g. lubricating agents (such asmagnesium stearate etc.), disintegrating agents (such as cellulosecalcium glycolate etc.), stabilizing agents (such as lactose etc.), andassisting agents for dissolving (such as glutamic acid, aspartic acidetc.).

The tablets or pills may, if desired, be coated with film of gastric orenteric material (such as sugar, gelatin, hydroxypropyl cellulose orhydroxypropylmethyl cellulose phthalate etc.), or be coated with morethan two films. And further, coating may include containment withincapsules of absorbable materials such as gelatin.

Liquid compositions for oral administration includepharmaceutically-acceptable solutions, emulsions, suspensions, syrupsand elixirs.

In such compositions, one or more of the active compound(s) is or arecomprise in inert diluent(s) commonly used in the art (purified water,ethanol etc.).

Besides inert diluents, such compositions may also comprise adjuvants(such as wetting agents, suspending agents etc.), sweetening agents,flavouring agents, perfuming agents and preserving agents.

Other compositions for oral administration include spray compositionswhich may be prepared by known methods and which comprise one or more ofthe active compound(s).

Spray compositions may comprise additional substances other than inertdiluents: e.g. stabilizing agents (sodium sulfite etc.), isotonic buffer(sodium chloride, sodium citrate, citric acid etc.)

For preparation of such spray compositions, for example, the methoddescribed in the U.S. Pat. No. 2,868,691 or 3,095,355 (hereinincorporated in their entireties by reference) may be used.

Injections for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions and emulsions. In such compositions,one more of active compound(s)is or are admixed with at least one ofinert aqueous diluent(s) (distilled water for injection, physiologicalsalt solution etc.) or inert non-aqueous diluent(s) (propylene glycol,polyethylene glycol, olive oil, ethanol, POLYSOLBATE80 (registered trademark) etc.).

Injections may comprise additional other than inert diluents: e.g.preserving agents, wetting agents, emulsifying agents, dispersingagents, stabilizing agent (lactose etc.), assisting agents such asassisting agents for dissolving (glutamic acid, aspartic acid etc.).

They may be sterilized for example, by filtration through abacteria-retaining filter, by incorporation of sterilizing agents in thecompositions or by irradiation. They also be manufactured in the form ofsterile solid compositions, for example, by freeze- drying, and whichcan be dissolved in sterile water or some other sterile diluents forinjection immediately before used.

Other compositions for parenteral administration include liquids forexternal use, and endermic liniments (ointment etc.), suppositories andpessaries which comprise one or more of the active compound(s) and maybe prepared by known methods.

Reference Example and Examples

The following Reference examples and examples are intended toillustrate, but not limit, the present invention. In Reference examplesand examples, "mp" shows "melting point".

Reference example 1 4-fluoroisatoic anhydride ##STR18##

To a solution of 2-amino-4-fluorobenzoic acid (4.65 g) in 50 mL of mixedsolvent (10:1=toluene:tetrahydrofuran) was added phosgene (4.46 g, 1.93Msolution of toluene ) dropwise via a drop funnel. The mixture wasstirred at room temperature for 1 hour and then heated to reflux overnight. The mixture was concentrated to about 10 mL and cooled inrefrigerator. The precipitate was filtered, washed with ether (5 mL×2)and air-dried to give the title compound (5.43 g) as a white solidhaving the following physical data.

NMR (200 MHz, DMSO-d6): δ6.92 (dd, 1H), 7.11 (td, 1H), 8.00 (dd, 1H),11.92 (broad, 1H).

Reference example 2 4-fluoroanthranilamide ##STR19##

A solution of the isatoic anhydride compound (3.62 g, prepared inReference example 1) in 100 mL of tetrahydrofuran was placed in a 200 mLround bottle equipped with gas in- and outlet. The anhydrous ammonia gaswas gently bubbled into the solution for 1.5 to 2 hours. After removalof the solvent the residue was taken up in methylene chloride (30 mL)and water (30 mL). The precipitate was collected by filtration andwashed with methylene chloride (10 mL) to give the title compound (1.95g) as a pale white solid having the following physical data.

NMR (200 MHz, DMSO-d6): δ6.70 (m, 1H), 6.82 (m, 1H), 6.90 (broad, 2H),7.72 (m, 1H).

The following compounds were obtained by the same procedure as Referenceexample 1 and Reference example 2, by using the correspondingsubstituted anthranilic acid compound.

Reference example 2(a). 5-methylanthranilamide ##STR20##

The product was collected by filtration as a pale solid.

NMR (200 MHz, DMSO-d6): δ 2.24 (s, 3H), 5.50 (broad, 2H), 6.62 (d, 1H),7.07 (dd, 1H), 7.16 (d, 1H).

Reference example 2(b) 5-chloroanthranilamide ##STR21##

The product was collected by filtration as a pale solid.

NMR (200 MHz, DMSO-d6): δ 5.68 (broad, 2H), 6.64 (d, 1H), 7.20 (dd, 1H),7.35 (d, 1H).

Reference example 2(C) 5-bromoanthranilamide ##STR22##

The product was collected by filtration as a pale brown.

NMR (200 MHz, DMSO-d6): δ 6.66 (dd, 1H), 6.72 (broad, 2H), 7.20 (broad,1H), 7.26 (dt, 1H), 7.70 (t, 1H), 7.82 (broad, 1H).

Reference example 2(d) 5-nitroanthranilamide ##STR23##

The product was collected by filtration as a solid.

NMR (200 MHz, DMSO-dG): δ 6.80 (dd,l H), 7.40 (broad, 1H), 7.90 (broad,2H), 8.03 (dt, 1H), 8.20 (broad, 1H), 8.56 (t, 1H).

Reference example 3 4-fluoro-2-[N-(3-pyridylcarbonyl)amino]benzamide##STR24##

To a solution of the anthranilamide compound (1.54 g, prepared inReference example 2) and triethylamine (1.4 g) in 100 mL oftetrahydrofuran was added nicotinoyl chloride hydrochloride (1.95 g).The resulting mixture was heated to reflux for one to three days andthen concentrated. The residue was taken up in water (25 mL) andchloroform (30 mL). The insoluble crude product was collected byfiltration and then vacuum dried. The crude product was triturated with10 mL of ether and pentane solution (1:1 ) to afford the title compound(2.27 g) as a white solid having the following physical data.

NMR (200 MHz, DMSO-d6): δ 7.10 (td, 1H), 7.80 (m, 1H), 7.99 (broad, 1H),8.07 (m, 1H), 8.40-8.55 (m, 3H), 8.90 (m, 1H), 9.15 (m, 1H).

Reference example 4 7-fluoro-2-(3-pyridyl)quinazolin-4-one ##STR25##

To a suspension of the benzamide compound (1.6 g, prepared in Referenceexample 3) in 60 mL of toluene was added sodium methoxide (853 mg). Thesolution was heated to reflux for one to three days. After cooling toroom temperature, the mixture was quenched with ammonium chloridesolution (30 mL) with a vigorously shaking. The mixture was cooled inrefrigerator and the insoluble product was collected by filtration anddried in vacuum to give the title compound (1.39 g) as a white solidhaving the following physical data.

NMR (200 MHz, DMSO-d6): ,5 7.43 (td, 1H), 7.53-7.64 (m, 2H), 8.20-8.28(m, 1H), 8.50 (dt, 1H), 8.78 (dd, 1H), 9.29 (m, 1H).

Reference example 5 4-chloro-7-fluoro-2-(3-pyridyl)quinazolinehydrochloride ##STR26##

A suspension of the quinazolinone compound (1.2 g, prepared in Referenceexample 4) in 20 mL of thionyl chloride was heated to reflux for threehours. The excess of thionyl chloride was removed by distillation. Theresidue was distilled azeotropically with benzene (5 mL×3) and thenreduced the total volume to about 5 mL. After cooling in refrigerator,precipitate was collected by filtration and washed with benzene twice togive the title compound (1.38 g) as a crystalline solid having thefollowing physical data.

NMR (200 MHz, DMSO-d6): δ 7.80-7.95 (m, 2H), 8.07 (dd, 1H), 8.43-8.49(m, 1H), 8.95 (d, 1H), 9.06 (dt, 1H), 9.65 (m, 1H).

The following compounds were obtained by the same procedure as Referenceexample 3→Reference example 4→ Reference example 5, by using theanthranilamide compound prepared in Reference example 2(a), 2(b) or2(c), or being on sale, and the corresponding acid chloride.

Reference example 5(a) 4-chloro-6-methyl-2-(3-pyridyl)quinazolinehydrochloride ##STR27##

The product was collected by filtration as a white solid.

NMR (200 MHz, DMSO-d6): δ 2.62 (s, 3H), 7.96-8.14 (m, 4H), 8.98 (d, 1H),9.16 (d, 1H), 9.63 (m, 1H).

Reference example 5(b) 4,6-dichloro-2-(3-pyridyl)quinazolinehydrochloride ##STR28##

The product was collected by filtration as a white solid.

mp :210-214° C. NMR (CDCl₃): δ 7.28-8.17 (m, 3H), 8.35 (m, 1H), 8.89(dd, 1H), 9.55 (dt, 1H), 9.98 (d, 1H).

Reference example 5(c) 4-chloro-6,7-dimethoxy-2-(3-pyridyl)quinazolinehydrochloride ##STR29##

The product was collected by filtration as a white solid.

NMR (200 MHz, DMSO-d6): δ 4.04 (s, 3H), 4.06 (s, 3H), 7.46 (s, 1H), 7.56(s, 1H), 7.95 (m, 1H), 8.93 (d, 1H), 9.09 (d, 1H), 9.60 (m, 1H).

Reference example 5(d) 4-chloro-2-(2-pyridyl)quinazoline ##STR30## Theproduct was collected by filtration as a light brown powder.

mp: 120°-121° C.

Reference example 5(e) 6-bromo-4-chloro-2-(3-pyridyl)quinazolinehydrochloride ##STR31##

NMR (200 MHz, DMSO-d6): δ 8.02 (m, 1H), 8.14 (dd, 1H), 8.33 (dt, 1H),8.50 (t, 1H), 9,01 (d, 1H), 9.14(d, 1H), 9.64 (t, 1H).

Reference example 6 2-[N-(3-pyridylcarbonyl)amino]benzamide ##STR32##

To a solution of anthranilamide (8.2 g, being on sale) and triethylamine(18.0 g)in 100 mL of tetrahydrofuran/methylene chloride (1:1), was addednicotinoyl chloride hydrochloride (10.8 g). The mixture was allowed tostir at room temperature, under nitrogen atmosphere, for six hours. Thesolution was then concentrated under reduced pressure. The concentratewas taken up in ethyl acetate and water and the mixture filtered. Thesolid material was triturated in ether and filtered to give the titlecompound (11.5 g) as a yellow powder having the following physical data.

mp :220°-222° C.

Reference example 7 2-(3-pyridyl)quinazolin-4-one ##STR33##

To a solution of the benzamide compound (11.5 g, prepared in Referenceexample 6) in 100 mL of toluene was added 95% sodium methoxide (5.7 g).The solution was heated at 60°-80° C. for three hours under nitrogenatmosphere. After cooling to room temperature, the solution was dilutedwith ammonium chloride solution. After stirring for one-half hour, themixture was filtered. An NMR of the filtered material indicated thereaction was incomplete. The material was taken up in toluene andethanol and 95% sodium methoxide (5.7 g) was added. The resultingsolution was heated to reflux and stirred via a mechanical stirrer,under nitrogen atmosphere, overnight. The solvent had evaporated and theconcentrate in the flask was collected and washed with ammonium chloridesolution and methylene chloride. The solid material was collected byfiltration and allowed to dry to give the title compound as a graypowder having the following physical data.

mp :275°-276° C. NMR (200 MHz, DMSO-d6): δ 7.50-7.61 (m, 2H), 7.75-7.90(m, 2), 8.16 (d, 1H), 8.49 (m, 1H), 8.77 (d, 1H), 9.31 (s, 1H). IR(KBr): ν 3185 (w), 3045 (m), 2915 (w), 1677 (s), 1603 (m), 1558 (w),1474 (m), 769 (m)cm⁻¹.

Reference example 8 4-chloro-2-(3-pyridyl)quinazoline ##STR34##

A solution of the quinazolinone compound (6.7 g, prepared in Referenceexample 7) and 5.7 mL of N,N-dimethylaniline in 200 mL of benzene washeated to reflux, under nitrogen atmosphere, for one-half hour with theremoval of 15 mL of distillate. After cooling to room temperature,phosphorus oxychloride (4.5 g) was added and the resulting solutionheated to reflux for six hours. After cooling to room temperature, thesolution was washed with ice water and dilute sodium hydroxide solution.The organic extract was dried over sodium sulfate and concentrated underreduced pressure. The concentrate was triturated in ether and collectedto give the title compound (3.0 g) having the following physical data.

mp: 178°-179° C.

The following compounds were obtained by the same procedure as Referenceexample 6→Reference example 7→Reference example 8, by usinganthranilamide and the corresponding acid chloride.

Reference example 8(a) 4-chloro-2-(4-pyridyl)quinazoline ##STR35##

The product was collected by filtration as a brown solid.

mp: 158°-160° C.

Reference example 8(b) 4-chloro-2-(2-chloro-5-pyridyl)quinazoline##STR36##

NMR (CDCl₃): δ7.47 (d, 1H), 7.73 (t, 1H), 7.95 (t, 1H), 8.05-8.32 (m,2H), 8.81 (dd, 1H), 9.55 (ds, 1H).

Reference example 8(c) 4-chloro-2-(2-thienyl)quinazoline ##STR37##

The product was collected by filtration as a tan powder.

mp: 121°-124° C.

Reference example 8(d) 4-chloro-2-(2-furyl)quinazoline ##STR38##

The product was collected by the filtration as a tan powder.

mp:116°-119° C.

Reference example 9 5-nitro-2-[N-(3-pyridylcarbonyl)amino]benzamide##STR39##

The title compound was obtained by the same procedure as Referenceexample 3, by using 5-nitroanthranilamide (prepared in Reference example2 (d)).

The product was collected by filtration as a white solid.

NMR (200 MHz, DMSO-d6): δ 7.70 (m, 1H), 8.20 (broad, 1H), 8.35 (dt, 1H),8.49 (dd, 1H), 8.85-8.92 (m, 3H), 9.15 (t, 1H).

Reference example 10 4-chloro-6-nitro-2-(3-pyridyl)quinazoline ##STR40##

A suspension of the benzamide compound (0.925 g, prepared in Referenceexample 9) in phosphorous oxychloride (6 mL) was heated to reflux for 16hours. After cooling to room temperature, the mixture was diluted bychloroform (30 mL) and then poured into 30 mL of ice-water mixture. Themixture was cooled in ice bath and carefully neutralized to pH 8 with atemperature control under 10° C. The aqueous layer was extracted withchloroform (50 mL×3). Combined organic layers were dried over withpotassium carbonate and concentrated under reduced pressure to give thetitle compound (0.8 g) having the following physical data.

NMR (CDCl₃): δ 7.27-7.35 (m, 2H), 7.52 (dd, 1H), 8.46-8.63 (m, 3H), 8.87(d, 1H), 9.42 (s, 1H).

EXAMPLE 1 4-phenylmethylamino-7-fluoro-2-(3-pyridyl)quinazoline##STR41##

To a warm solution of the 4-chloroquinazoline compound (1.18 g, preparedin Reference example 5)in 50 mL ethanol was added phenylmethylamine(2.00 g). The mixture was heated to reflux for sixteen hours. Thesolution was then concentrated and the residue taken up in chloroformand ammonium chloride solution. The aqueous layer was extracted withchloroform (30 mL×3) and dried over sodium sulfate. After concentration,the residue was triturated in pentane/ether solution to give the titlecompound (0.88 g) as a pale white solid having the following physicaldata.

mp: 199°-203° C. NMR (CDCl₃): δ 5.00 (d, 2H), 6.01 (broad, 1H), 7.20(td, 1H), 7.25-7.50 (m, 6H), 7.55 (dd, 1H), 7.70-7.77 (m, 1H), 8.70 (dd,1H), 8.79 (dt, 1H), 9.74 (m, 1H). IR (KBr): ν 697 (s), 775 (s), 1166(m), 1259 (m), 1341 (s), 1375 (s), 1444 (s), 1535 (s), 1592 (s), 1626(s), 3135 (m), 3250 (m)cm⁻¹.

EXAMPLE 2 4-phenylmethylamino-7-fluoro-2-(3-pyridyl)quinazolinedihydrochloride ##STR42##

To a suspension of the free base (0.70 g, prepared in Example 1) in 10ml methanol was added excess amount of HCl in methanol. The mixture wasstirred at room temperature for a half of an hour. The solvent wasremoved and the residue was triturated in ether (30 ml). The titlecompound (0.84 g) as a white powder having the following physical data,was obtained after filtration.

mp: 250° C.

NMR (CDCl₃): δ 4.50 (d, 2H), 7.25-7.40 (m, 3H), 7.49-7.53 (m, 2H), 7.64(dt, 1H), 7.82 (dd, 1H), 7.99 (m, 1H), 8.67 (m, 1H), 8.97 (dd, 1H), 9.15(dd, 1H), 9.60 (d, 1H), 10.18 (broad, 1H). IR (KBr): ν 704 (m), 1266(m), 1457 (s), 1574 (s), 1632 (s), 2920-2440 (broad, s), 3115 (broad, s)cm⁻¹.

EXAMPLE 3

The following compounds were obtained by the same procedure as Example1, or Example 1 and Example 2, by using the corresponding4-chloroquinazoline compound prepared by Reference example 5, 5(a) to5(e) or Reference example 8, 8(a) to 8(d) and the proper amine.

EXAMPLE 3(a) 4-phenylmethylamino-6-methyl-2-(3-pyridyl)quinazoline andits salt ##STR43##

(free base)

The product was collected by filtration as a white solid.

mp: 179°-180° C. (dec.). NMR (CDCl₃): δ 5.03 (d, 2H), 5.97 (broad, 1H),7.28-7.53 (m, 7H), 7.61 (dd, 1H), 7.86 (d, 1H), 8.69 (dt, 1H), 8.80 (dt,1H), 9.76 (m, 1H). IR (KBr): ν 699 (w), 1365 (m), 1407 (w), 1437 (w),1535 (s), 1569 (s), 1591 (s), 3200 (m) cm⁻¹.

(2HCl salt)

The product was collected by filtration as a white powder.

mp :265°-269° C. (dec.). NMR (CDCl₃): δ 2.50 (s, 3H), 5.03 (d, 2H),7.28-7.42 (m, 3H), 7.48-7.53 (m, 2H), 7.80-7.91 (m, 2H), 8.06 (d, 1H),8.45 (s, 1H), 8.91-9.00 (m, 2H), 9.5 (m, 1H). IR (KBr): ν 704 (w), 1388(m), 1568 (s), 1593 (s), 1617 (s), 2400-3100 (broad, s), 3200 (m), 3410(broad, m) cm⁻¹.

EXAMPLE 3(b) 4-phenylmethylamino-6-chloro-2-(3-pyridyl)quinazoline andits salt ##STR44##

(free base)

The product was purified by column chromatography.

mp :240° C.

NMR (CDCl₃): δ 5.00 (d, 2H), 5.92 (broad, 1H), 7.32-7.51 (m, 6H), 7.71(m, 2H), 7.90 (d, 1H), 8.71 (dd, 1H), 8.79 (dt, 1H), 9.75 (d, 1H). IR(KBr): ν 697 (m), 1368 (s), 1419 (m), 1439 (m), 1534 (s), 1568 (s), 1590(s), 3260 (w) cm⁻¹.

(2HCl salt)

The product was collected by filtration as a white powder.

mp: 255° C. (dec.). NMR (CDCl₃): δ 4.99 (d, 2H), 7.25-7.42 (m, 3H),7.45-7.55 (m, 2H), 7.96-8.10 (m, 3H), 8.72 (m, 1H), 8.96 (d, 1H), 9.15(d, 1H), 9.60 (m, 1H). IR (KBr):δ 671 (w), 709 (m), 1356 (m), 1387 (s),1457 (m), 1488 (m), 1518 (m), 1569 (s), 1608 (s), 1631 (s), 2335-2890(broad, s), 3825 (s), 3230 (m), 3425 (m) cm⁻¹.

EXAMPLE 3(c) 4-phenylmethylamino-6,7-dimethoxy-2-(3-pyridyl)quinazolineand its salt ##STR45##

(free base)

The product was collected by filtration as a white solid.

mp: 193°-196° C. NMR (200 MHz, DMSO-d6): ,5 3.92 (s, 3H), 3.94 (s, 3H),4.92 (d, 2H), 6.90 (broad, 1H), 7.23-7.38 (m, 4H), 7.46-7.55 (m, 3H),7.76 (s, 1H), 8.62-8.78 (m, 3H), 9.52 (m, 1H). IR (KBr): ν 698 (m), 850(m), 1026 (m), 1131 (m), 1183 (m), 1213 (s), 1243 (s), 1366 (s), 1450(s), 1501 (s), 1528 (s), 1591 (s), 1622 (m), 3270 (w) cm⁻¹.

(2HCl salt)

The product was collected by filtration as a white solid.

mp: 240° C. (dec.). NMR (200 MHz, DMSO-d6): <5 3.98 (s, 6H), 5.01-5.06(m, 2H), 7.25-7.41 (m, 3H), 7.74 (s, 1H), 7.85 (m, 1H), 8.14 (s, 1H),a.90-8.95 (m, 2H), 9.56 (m, 1H). IR (KBr): ν 1243 (w), 1287 (s), 1378(m), 1473 (m), 1 504 (s), 1542 (m), 1596 (m), 1634 (s), 2400-3200(broad, s), 3440 (broad, s) cm⁻¹.

EXAMPLE 3(d) 4-phenylmethylamino-2-(2-pyridyl)quinazoline and its salt##STR46##

(free base):

The product was collected by filtration as a tan solid.

mp: 165°-169° C.

(2HCl salt)

mp: 140°-155° C. NMR (200 MHz, DMSO-d6): δ 5.12 (d, 2H), 7.35 (m, 3H),7.58 (d, 2H), 7.83 (qd, 2H), 8.07 (t, 1H), 8.19-8.36 (m, 2H), 8.64 (d,1H), 8.82 (d, 1H), 8.93 (d, 1H), 11.40 (t, 1H). IR (KBr): ν 3370 (m),3220 (m), 3200-2700 (m), 1625 (s), 1562 (s), 1524 (m), 1466 (m), 1385(m), 765 (m) cm⁻¹.

EXAMPLE 3(e) 4-phenylmethylamino-2-(3-pyridyl)quinazoline and its salt##STR47##

(free base)

mp: 137°-138° C. NMR (CDCl₃): <3 5.01 (d, 2H), 6.20 (t, 1H), 7.26-7.49(m, 6H), 7.71-7.79 (t, 3H), 7.95 (d, 1H), 8.68 (bs, 1H), 8.82 (d, 1H),9.75 (bs, 1H). IR (KBr): ν 3305 (m), 1584 (s), 1520 (s), 1437 (m), 1410(m), 1365 (s), 1325 (w), 765 (m), 694 (m) cm⁻¹.

(2HCl salt)

mp :225°-235° C. NMR (200 MHz, DMSO-d6): δ 5.05 (d, 2H), 7.22-7.43 (m,3H), 7.52 (m, 2H), 7.78 (t, 1H), 7.94-8.13 (m, 2H), 8.36 (s, 1H), 8.78(d, 1H), 9.00 (dd, 1H), 9.12 (dd, 1H), 9.70 (s, 1H), 11.16 (broad t,1H). IR (KBr): ν 3300-2615 (broad,s), 1629 (s), 1605 (s), 1569 (s), 1456(m), 1384 (m), 763 (m), 705 (m)cm⁻¹.

EXAMPLE 3(f) 4-phenylamino-2-(3-pyridyl)quinazoline ##STR48##

The product was collected by filtration as a yellow powder.

mp: 173°-178° C. NMR (200 MHz, DMSO-d6): δ 7.29 (t, 1H), 7.53 (t, 2H),7.72-8.17 (m, 6H), 8.80 (d, 1H), 8.93 (d, 1H), 9.05 (d, 1H), 9.52 (s,1H), 10.81 (bs, 1H). IR (KBr): ν 3160 (bw), 1559 (s), 1520 (s), 1411(m), 1363 (m), 754 (m) cm⁻¹.

EXAMPLE 3(g) 4-(3-methoxycarbonylphenyl)amino-2-(3-pyridyl)quinazoline##STR49##

The product was collected by filtration as a yellow powder.

mp: 228°-245° C. NMR (200 MHz, DMSO-d6): δ 3.94 (s, 3H), 7.56-8.04 (m,7H), 8.72-9.08 (m, 4H), 9.57 (s, 1H), 10.61 (bs, 1H). IR (KBr): ν 3400(bw), 1717(m), 1562 (s), 1520 (m), 1447 (m), 1374 (m), 1299 (m),1278(m), 752 (m), 672 (w)cm⁻¹.

EXAMPLE 3(h) 4-(4-carboxyphenylmethyl)amino-2-(3-pyridyl)quinazoline##STR50##

mp: 285°-294° C. NMR (200 MHz, DMSO-d6): δ 4.98 (d, 2H), 7.50-7.62 (m,4H), 7.81 (d, 2H), 7.90 (d, 2H), 8.37 (d, 1H), 8.65 (m, 2H), 9.13 (t,1H), 9.49 (s, 1H). IR (KBr): ν 3340 (broad), 1747 (m), 1586 (s), 1531(s), 1366 (m), 765 (m) cm⁻¹.

EXAMPLE 3(i) 4-(2-thienylmethyl)amino-2-(3-pyridyl)quinazoline and itssalt ##STR51##

(free base)

mp: 195°-197° C. NMR (200 MHz, DMSO-d6): δ 5.08 (d, 2H), 6.99 (m, 1H),7.19 (m, 1H), 7.35 (dd, 1H), 7.55 (m, 2H), 8.30 (s, 1H), 8.69 (m, 1H),8.83 (m, 1H), 9.13 (t, 1H). IR (KBr): ν 3260 (bw), 1583 (s), 1525 (s),1449 (m), 1359 (s), 763 (m), 747 (m), 720 (m) cm⁻¹

(2HCl salt)

mp: 255° C. (dec.). NMR (200 MHz, DMSO-d6): <5 5.20 (d, 2H), 7.01 (m,1H), 7.22 (m, 1H), 7.43 (s, 1H), 7.77 (t, 1H), 8.00 (m, 3H), 8.21 (d,1H), 8.61 (d, 1H), 8.99 (d, 1H), 9.23 (d, 1H), 9.74 (s, 1H), 10.45 (bs,1H). IR (KBr): ν 3405 (w), 3060-2615 (broad, m), 2363 (w), 1631 (s),1608 (s), 1570 (s), 1458 (m), 1387 (m), 773 (m), 712 (m)cm⁻¹.

EXAMPLE 3(j) 4-(3-chlorophenylmethyl)amino-2-(3-pyridyl)quinazoline andits salt ##STR52##

(free base)

mp: 203°-205° C. NMR (200 MHz, DMSO-d6): <5 4.92 (d, 2H), 7.27-7.61 (m,6H), 7.82 (d, 2H), 8.33 (d, 1H), 8.66 (m, 2H), 9.08 (t, 1H), 9.53 (s,1H). IR (KBr): ν 3245 (w), 3050-2800 (w), 1586 (s), 1533 (m), 1436 (w),1412 (w), 1366 (m), 765 (w) cm⁻¹.

(2HCl salt)

mp: 235°-250° C. NMR (200 MHz, DMSO-d6): ,5 5.05 (d, 2H), 7.35 (m, 2H),7.49 (m, 1H), 7.62 (s, 1H), 7.78 (t, 1H), 7.90-8.12 (m, 2H), 8.28 (s,1H), 8.97 (m, 1H), 9.13 (dd, 1H), 9.66 (s, 1H), 10.97 (bs, 1H). IR(KBr): ν 3035 (m), 2900-2700 (m), 1634 (m), 1610 (m), 1569 (m), 1387(w), 780 (w), 71 0 (w) cm⁻¹.

EXAMPLE 3(k) 4-(3-pyridylmethyl)amino-2-(3-pyridyl)quinazoline and itssalt ##STR53##

(free base)

mp: 157°-161° C. NMR (200 MHz, DMSO-d6): δ 4.95 (d, 2H), 7.33 (m, 1H),7.55 (m, 2H), 7.85 (m, 3H), 8.33 (d, 1H), 8.46 (dd, 1H), 8.65-8.76 (m,3H), 9.10 (t, 1H), 9.57 (s, 1H). IR (KBr): ν 3255 (m), 3050-2900 (w),1586 (s), 1533 (s), 1438 (m), 368 (s), 763 (m), 700 (m)cm⁻¹.

(3HCl salt)

mp: 240°-257° C. NMR (200 MHz, DMSO-d6): δ 5.25 (d, 2H), 7.77 (t, 1H),8.07 (m, 2H), 8.29 (d, 1H), 8.83 (m, 4H), 9.00 (d, 1H), 9.19 (m, 2H),9.69 (s, 1H), 11.25 (bs, 1H). IR (KBr):δ 3500 (w), 3100-2500 (broad, m),1633 (s), 1611(s), 1569 (m), 1542 (m), 1457 (w), 790 (w), 720 (w) cm⁻¹.

EXAMPLE 3(l) 4-(3,4-dimethoxyphenylmethyl)amino-2-(3-pyridyl)quinazolineand its salt ##STR54##

(free base)

mp: 155°-159° C. NMR (200 MHz, DMSO-d6): δ 3.71 (d, 6H), 4.85 (d, 2H),6.83-7.05 (m, 2H), 7.18 (s, 1H), 7.54 (m, 2H), 7.82 (d, 2H), 8.32 (d,1H), 8.68 (dd, 1H), 8.77 (dd, 1H), 9.01 (t, 1H), 9.63 (s, 1H). IR (KBr):ν 3395 (w), 3200-2900 (w), 1584 (s), 1514 (s), 1364 (m), 1263 (m), 1025(m), 764 (w) cm⁻¹.

(2HCl salt)

mp: 21 5°-220° C.

NMR (200 MHz, DMSO-d6): δ 3.70 (s, 6H), 4.97 (d, 2H), 6.90 (d, I H),7.02 (d, 1H), 7.24 (s, 1H), 7.77 (t, 1H), 7.92 (m, 1H), 8.04 (t, 1H),8.73 (d, 1H), 8.97 (d, 1H), 9.16 (dd, 1H), 9.70 (s, 1H), 10.94 (bs, 1H).IR (KBr): ν 3404 (m), 3200-2300 (m), 1631 (s), 1610 (s), 1569 (s), 1514(s), 1264 (m), 765 (m) cm⁻¹

EXAMPLE 3(m) 4-phenylethylamino-2-(3-pyridyl)quinazoline and its salt##STR55##

(free base)

mp: 136°-139° C. NMR (200 MHz, DMSO-d6): δ 3.07 (t, 2H), 3.89 (q, 2H),7.20-7.30 (m, 3H), 7.32 (d, 2H), 7.55 (m, 2H), 7.82 (s, 2H), 8.26 (s,1H), 8.59 (t, 1H), 8.70 (m, 2H), 9.65 (s, 1H). IR (KBr): ν 3290 (m),3050-2900 (w), 1591 (s), 1514 (s), 1534 (s), 1442 (m), 1370 (s), 761(m), 702 (m) cm⁻¹.

(2HCl salt)

mp:220°-250° C. (dec.). NMR (200 MHz, DMSO-d6): ,5 3.11 (t, 2H), 4.05(q, 2H), 7.15-7.38 (m, 5H), 7.77 (t, 1H), 8.01 (m, 2H), 8.35 (d, 1H),8.70 (d, 1H), 9.01 (d, 1H), 9.15 (d, 1H), 9.69 (s, 1H), 10.68 (bs, 1H).IR (KBr): ν 3400 (w), 3100-2500 (m), 1633 (s), 1613 (s), 1570 (m), 1457(m), 1385 (m), 790 (w), 720 (w) cm⁻¹.

EXAMPLE 3(n)4-(3-trifluoromethylphenylmethyl)amino-2-(3-pyridyl)quinazolinedihydrochloride ##STR56##

mp :>280° C. NMR (200 MHz, DMSO-d6): ,5 5.14 (d, 2H), 7.52-8.35 (m, 8H),8.70-9.20 (m, 3H), 9.67 (m, 1H).

EXAMPLE 3(o)4-(4-(N,N-dimethylamino)phenylmethyl)amino-2-(3-pyridyl)quinazolinetrihydrochloride ##STR57##

mp: 200°-250° C. (dec.). NMR (200 MHz, DMSO-d6): δ 3.04 (s, 6H), 5.05(d, 2H), 7.50-8.30 (m, 8H), 8.72 (s, 1H), 8.92-9.12 (m, 2H), 9.60 (m,1H).

EXAMPLE 3(p) 4-(4-sulfamoylphenylmethyl)amino-2-(3-pyridyl)quinazolinedihydrochloride ##STR58##

mp: 255°-265° C. NMR (200 MHz, DMSO-d6): <5 5.10 (d, 2H), 7.32 (bs, 2H),7.66-8.20 (m, 8H), 8.62 (d, 1H), 8.95 (m, 2H), 9.56 (ms, 1H).

EXAMPLE 3(q) 4-phenylmethylamino-2-(4-pyridyl)quinazoline and its salt##STR59##

(free base)

mp: 195°-197° C. NMR (200 MHz, DMSO-d6): δ 4.96 (d, 2H), 7.19-7.66 (m,6H), 7.83 (d, 2H), 8.30 (d, 2H), 8.39 (d, 1H), 8.72 (d, 2H), 9.10 (t,1H). IR (KBr):δ 3250 (w), 1585 (s), 1561 (s), 1529 (s), 1411 (m), 1374(s), 1325 (s), 768 (m), 702 (m) cm⁻¹.

(2HCl salt):

mp: 260°-270° C. NMR (200 MHz, DMSO-d6): δ 5.02 (d, 2H), 7.22-7.40 (m,3H), 7.51 (d, 2H), 7.75 (t, 1H), 8.00 (t, 1H), 8.16 (d, 1H), 8.66 (d,1H), 8.81 (d, 2H), 9.06 (d, 2H), 10.32 (bs, 1H). IR (KBr): ν 3385 (m),3210 (m), 3060-2600 (s), 1627 (s), 1604 (s), 1567 (s), 1505 (m), 1452(m), 1383 (m), 760 (m), 709 (m) cm⁻¹.

EXAMPLE 3(r) 4-phenylamino-2-(4-pyridyl)quinazoline ##STR60##

mp: 270°-274° C. NMR (200 MHz, DMSO-d6): δ 7.22 (t, 1H), 7.70 (m, 1H),7.94 (m, 4H), 8.37 (m, 2H), 8.68 (d, 1H), 8.82 (d, 2H), 10.13 (s, 1H).IR (KBr): ν 3270 (m), 3145 (m), 1620 (s), 1572 (s), 1524 (s), 1488 (s),1443 (s), 1414 (s), 1374 (s), 749 (m), 702 (m) cm⁻¹.

EXAMPLE 3(s) 4-phenylmethylamino-2-(2-chloro-5-pyridyl)quinazoline##STR61##

mp: 212°-21 4° C. NMR (CDCl₃): δ 4.96 (d, 2H), 6.03 (bs, 1H), 7.20-7.55(m, 7H), 7.66-7.95 (m, 3H), 8.78 (m, 1H), 9.52 (m, 1H). IR (KBr): ν 3315(w), 1580 (s), 1532 (ms), 1446 (mw), 1343 (m), 1269 (w) cm⁻⁻¹.

EXAMPLE 3(t) 4-phenylmethylamino-2-(2-thienyl)quinazoline ##STR62##

mp: 158°-163° C. NMR (200 MHz, DMSO-d6): δ 4.88 (d, 2H), 7.14-7.53 (m,6H), 7.62-7.81 (m, 3H), 7.92 (m, 1H), 8.30 (d, 1H), 8.97 (t, 1H). IR(KBr):δ 3305 (w), 1571 (s), 1519 (s), 1451 (m), 1408 (m), 1377 (s), 769(m), 730 (m), 737 (m) cm⁻¹.

EXAMPLE 3(u) 4-phenylamino-2-(2-thienyl)quinazoline ##STR63##

mp: 137°-139° C. NMR (200 MHz, DMSO-d6): δ 7.20 (m, 2H), 7.62-8.09 (m,9H), 8.58 (d, 1H), 9.85 (s, 1H). IR (KBr): ν 3430 (w), 1616 (w), 1662(w), 1561 (s), 1461 (m), 1488 (m), 1461 (m), 1406 (m), 1374 (m), 749(w)cm⁻¹.

EXAMPLE 3(v) 4-phenylmethylamino-2-(2-furyl)quinazoline ##STR64##

mp: 152°-154° C. NMR (CDCl₃): δ 4.95 (d, 2H), 6.00 (t, 1H), 6.56 (m,1H), 7.31-7.49 (m, 7H), 7.62-7.76 (m, 3H), 7.97 (d, 1H). IR (KBr): ν3290 (m), 1589 (m), 1531(s), 1365 (s), 1015 (m), 890 (m), 762 (s) cm⁻¹.

EXAMPLE 3(w) 4-phenylamino-2-(2-furyl)quinazoline ##STR65##

mp: 183°-184° C. NMR (CDCl₃): δ 6.58 (m, 1H), 7.13-7.37 (m, 2H),7.39-7.58 (q, 4H), 7.65 (s, 1H), 7.72-7.94 (m, 4H), 8.03 (d, 1H). IR(KBr): ν 3456 (w), 1607 (m), 1559 (s), 1524 (s), 1485 (s), 1446 (m),1419 (m), 1360 (m), 748 (m) cm⁻¹.

EXAMPLE 3(x)6-chloro-4-(2-(1-methyl-2-pyrrolyl)ethyl)amino-2-(3-pyridyl)quinazolineand its salt ##STR66##

(free base)

The product was collected by filtration as a white solid.

NMR (200 MHz, DMSO-d6): <5 2.99 (t, 2H), 3.58 (s, 3H), 3.89 (q, 2H),5.90 (m, 2H), 6.62 (m, 1H), 7.55 (m, 1H), 7.83 (m, 2H), 8.44 (d, 1H),8.70-8.75 (m, 3H), 9.61 (m, 1H).

(2HCl salt)

The product was collected by filtration as a white powder.

mp: 190°-194° C. (dec.). NMR (200 MHz, DMSO-d6): δ 3.02 (t, 2H), 3.58(s, 3H), 3.97 (q, 2H), 5.88 (m, 2H), 6.60 (t, 1H), 7.97-8.14 (m, 2H),8.16 (d, 1H), 8.74 (d, 1H), 8.99 (dd, 1H), 9.16 (d, 1H), 9.63 (d, 1H),10.00 (broad, 1H). IR (KBr): ν 711 (w), 709 (m), 1359 (m), 1388 (s),1438 (m), 1549 (s), 1570 (s), 1599 (s), 1634 (s), 2065 (m), 2365 (m),2555 (s), 3110 (m), 3360 (m) cm⁻¹.

EXAMPLE 3(y) 4-phenylmethylamino-6-bromo-2-(3-pyridyl)quinazoline andits salt ##STR67##

(free base)

The product was collected by filtration as a solid.

NMR (200 MHz, DMSO-d6): <3 4.90 (d, 2H), 7.25-7.56 (m, 6H), 7.75 (d,2H), 7.94 (dd, 1H), 8.66-8.71 (m, 3H), 9.18 (broad, 1H), 9.54 (d, 1H).

(2HCl salt)

mp: 233°-240° C. (dec.). NMR (200 MHz, DMSO-d6): <5 4.99 (d, 2H),7.25-7.42 (m, 3H), 7.51-7.57 (m, 3H), 7.96-8.03 (m, 1H), 8.07-8.10 (m,2H), 8.93-9.00 (m, 2H), 9.19 (d, 1H), 9.62 (d, 1H), 10.30 (broad, 1H).IR (KBr): ν 701 (m), 1357 (m), 1404 (s), 1446 (m), 1519 (s), 1549 (s),1628 (s), 2400-3000 (broad, s), 3140 (s) cm⁻¹.

EXAMPLE 3(z) 4-phenylmethylamino-6-nitro-2-(3-pyridyl)quinazoline andits salt ##STR68##

(free base)

The product was collected by filtration as a solid.

NMR (200 MHz, DMSO-d6): δ 4.95 (d, 2H), 7.25-7.40 (m, 3H), 7.48-7.58 (m,3H), 7.93 (dd, 1H), 8.50 (dt, 1H), 8.70-8.80 (m, 2H), 9.46 (d, 1H), 9.58(d, 9.70 (broad, 1H).

(2HCl salt)

mp: 289°-292° C. (dec.). NMR (200 MHz, DMSO-d6): δ 5.00 (d, 2H),7.25-7.42 (m, 3H), 7.51-7.55 (m, 2H), 8.04-8.09 (m, 2H), 8.59 (dt, 1H),9.00 (dd, 1H), 9.27 (d, 1H), 9.54 (d, 1H), 9.67 (s, 1H), 10.18 (broad,1H). IR (KBr): ν 671 (m), 709 (m), 757 (m), 784 (m), 1349 (s), 1514 (s),1578 (s), 1636 (s), 2445 (broad, s), 2860 (w), 3070 (m) cm⁻¹.

EXAMPLE 3(aa) 4-(cyclopropylmethyl)amino-2-(3-pyridyl)quinazoline andits salt ##STR69##

(free base)

mp: 162°-163° C. NMR (200 MHz, DMSO-d6): δ 0.38 (m, 2H), 0.49 (m, 2H),1.33 (m, 1H), 3.58 (t, 2H), 7.55 (m, 2H), 7.79 (m, 2H), 8.32 (d, 1H),8.56 (t, 1H), 8.69 (m, 2H), 9.62 (s, 1H). IR(KBr):δ 3265(w), 1537 (s),1525 (s), 1437 (w), 1369 (s), 762 (m) cm⁻¹.

(2HCl salt)

mp: 230°-239° C. NMR (200 MHz, DMSO-d6): ,5 0.43 (m, 2H), 0.50 (m, 2H),1.32 (m, 1H), 3.71 (t, 2H), 7.78 (t, 1H), 7.93 (m, 1H), 8.05 (t, 1H),8.34 (d, 1H), 8.77 (d, 1H), 8.99 (d, 1H), 9.08 (dd, 1H), 9.68 (s, 1H),10.68 (bs, 1H). IR (KBr): ν 3405-2700 (broad, s), 2365 (w), 1632 (s),1600 (s), 1570 (m), 1542 (m), 1458 (w), 1383 (m), 1321 (w), 767 (w), 669(w) cm⁻¹.

EXAMPLE 3(bb) 4-(3-methylphenylmethyl)amino-2-(3-pyridyl)quinazoline andits salt ##STR70##

(free base)

mp: 166°-169° C. NMR (200 MHz, DMSO-d6): δ 2.28 (s, 3H), 4.90 (s, 2H),7.03 (bd, 1H), 7.18-7.32 (m, 3H), 7.47-7.61 (m, 2H), 7.81 (d, 1H), 8.35(d, 1H), 8.69 (m, 2H), 9.02 (bt, 1H), 9.58 (s, 1H). IR (KBr): ν 3245(m), 1567 (s), 1533 (s), 1438 (m), 1443 (m),1368 (s), 1326 (m), 762 (m),699 (m)cm⁻¹.

(2HCl salt)

mp: 225°-244° C. NMR (200 MHz, DMSO-d6): <5 2.29 (s, 3H), 5.03 (s, 2H),7.10 (d, 1H), 7.20-7.38 (m, 3H), 7.77 (t, 1H), 7.92-8.10 (m, 2H), 8.34(d, 1H), 8.76 (d, 1H), 9.02 (d, 2H), 9.20 (d, 2H), 9.69 (s, 1H), 11.05(bt, 1H). IR (KBr): ν 3400 (m), 3050-2600 (broad, m), 1627 (s), 1570(s), 1542 (m), 1457 (m), 1385 (m), 770 (m), 680 (m) cm⁻¹

EXAMPLE 3(cc)4-(2-(1-methyl-2-pyrrolyl)ethyl)amino-2-(3-pyridyl)quinazoline ##STR71##

mp: 140°-142° C. NMR (200 MHz, DMSO-d6): δ 3.00 (t, 2H), 3.58 (s, 3H),3.88 (qd, 2H), 5.91 (m, 2H), 6.63 (t, 1H), 7.53 (m, 2H), 7.80 (d, 2H),8.24 (d, 1H), 8.59 (t, 1H), 8.79 (m, 2H), 9.62 (s, 1H). IR (KBr): ν 3445(m), 3130-2900 (w), 2369 (w), 1567 (s), 1514 (s), 1533 (s), 1443 (m),1438 (m), 1368 (s), 1351 (m), 1187 (w), 762 (m), 699 (m) cm⁻¹.

EXAMPLE 3(dd) 4-(3-nitrophenylmethyl)amino-2-(3-pyridyl)quinazoline andits salt ##STR72##

(free base)

mp: 21 8°-220° C. NMR (200 MHz, DMSO-d6): δ 5.05 (d, 2H), 7.46-7.69 (m,3H), 7.83 (m, 2H), 7.84 (d, 1H), 8.13 (d, 1H), 8.37 (m, 2H), 8.67 (m,2H), 9.18 (t, 1H), 9.52 (s, 1H).

(2HCl salt)

mp: 263°-265° C. NMR (200 MHz, DMSO-d6): δ 5.15 (d, 2H), 7.60-7.86 (m,3H), 7.90-8.19 (m, 5H), 8.26 (d, 1H), 8.43 (s, 1H), 8.75 (d, 1H), 9.00(d, 1H), 9.18 (d, 1H), 9.65 (s, 1H), 11.03 (bs, 1H).

EXAMPLE 3(ee) 4-(5-methyl-3-isoxazolyl)amino-2-(3-pyridyl)quinazolineand its salt ##STR73##

(free base)

NMR (200 MHz, DMSO-d6): δ 2.28 (s, 3H), 7.64 (s, 1H), 7.52-7.71 (m, 2H),7.95 (m, 2H), 8.72 (m, 4H), 9.68 (m, 1H), 10.98 (s, 1H).

(2HCl salt)

mp: 228°-230° C. NMR (200 MHz, DMSO-d6): δ 2.53 (s, 3H), 7.09 (s, 1H),7.74 (m, 1H), 8.04 (m, 2H), 8.18 (m, 1H), 8.75 (d, 1H), 9.06 (d, 1H),9.34 (d, 1H), 9.64 (s, 1H).

The following compounds were obtained by the same procedure as describedin Reference examples 2, 3, 4 and 5 and examples 1 and 2 or in Referenceexample 6, 7 and 8 and examples 1 and 2, by using isatoic anhydride.

EXAMPLE 3(ff) 6-iodo-4-phenylmethylamino-2-(3-pyridyl)quinazolinedihydrochloride ##STR74##

mp:205°-10° C., (dec.) NMR (200 MHz, DMSO-d6) δ: 5.00 (d, 2H), 7.28-7.41(m, 3H), 7.47-7.53 (m, 2H), 7.80 (d, 1H), 7.95 (m, 1H), 8.23 (dd, 1H),8.92-8.98 (m, 2H), 9.08 (d, 1H), 9.59 (m, 1H), 10.00 (broad, 1H).

EXAMPLE 3(gg) 6-fluoro-4-phenylmethylamino-2-(3-pyridyl)quinazolinedihydrochloride ##STR75##

mp: 200°-2° C., (dec.) NMR (200 MHz, DMSO-d6) 8:5.02 (d, 2H), 7.28-7.41(m, 3H), 7.51-7.54 (m, 2H), 7.82-8.02 (m, 2H), 8.07-8.20 (m, 1H),8.40-8.52 (d, 1H), 8.97 (dd, 1H), 9.15 (d, 1H), 9.61 (s, 1H), 10.08(broad, 1H).

EXAMPLE 3(hh) 4-(3-carboxyphenyl)amino-2-(4-pyridyl)quinazoline##STR76##

mp: >300° C. NMR (200 MHz, DMSO-d6) 8:7.65 (t, 1H), 7.78 (m, 2H), 7.99(d, 2H), 8.22 (d, 1H), 8.68 (d, 2H), 8.75 (d, 1H), 8.87 (m, 3H), 10.44(s, 1H). IR (KBr)ν: 3370-2800 (w, broad), 1712 (m), 1632 (m), 1571 (s),1545 (s), 1473 (m), 1437 (m), 1376 (m), 764 (m) cm⁻¹.

EXAMPLE 4 6-acetylamino-4-phenylmethylamino-2-(3-pyridyl)quinazoline##STR77##

To warmed suspension of the nitroquinazoline compound (141 mg, preparedin Example 3(z)) in acetic acid (4 mL) was added zinc dust (80 mg). Thered mixture was heated to reflux for overnight. After cooling down toroom temperature the precipitate was removed by filtration. The filtratewas neutralized to pH 8 and extracted with chloroform. The insolublesolid was removed by filtration during the extraction. The chloroformwas dried over potassium carbonate and then concentrated to 0.5 mL(total volume). The precipitate was collected by filtration to give thetitle compound (20 mg) having the following physical data.

mp: 127° C. (dec.). NMR (200 MHz, DMSO-d6): δ 2.12 (s, 3H), 4.88 (d,2H), 7.22-7.37 (m, 3H), 7.45-7.53 (m, 2H), 7.75 (m, 1H), 8.32 (m, 2H),8.58-8.69 (m, 3H), 8.94 (broad 1H), 9.52 (m, 1H), 10.23 (broad, 1H). IR(KBr): ν 700 (w), 840 (w), 1318 (m), 1368 (m), 1426 (m), 1537 (s), 1584(s), 1676 (m), 3065 (m), 3365 (m) cm⁻¹.

Reference Example 11 6-chloro-(1H,3H)-quinazolin-2,4-dione ##STR78##

To a solution of 5-chloroanthranilamide (3.4 g)in tetrahydrofuran (50mL) was added phosgene (16 mL, 1.93M solution in toluene) via anaddition funnel. The reaction mixture was stirred at room temperaturefor 4 hours and then heated to reflux for another two hours. Thereaction mixture was concentrated to a total volume about 10 mL. Aftercooling, the title compound (3.72 g) having the following physical data,was collected by filtration and dried in vacuum.

NMR (200 MHz, DMSO-d6): δ 7.19 (d, 1H), 7.69 (dd, 1H), 7.82 (d, 1H),11.28 (broad, 1H), 11.45 (broad, 1H).

Reference example 12 4-chloro-2-chloromethylquinazoline ##STR79##

To a solution of anthranilonitrile (11.8 g) and chloroacetonitrile (7.5g) in 1,4-dioxane (200 mL), cooled in an ice bath, was bubbled HCl gas.The reaction mixture was stirred for two and one-half hours at whichtime the reaction was allowed to warm to room temperature and continuedto bubble HCl gas for 16 hours. After the HCl gas bubbling was ceased,nitrogen gas was bubbled through to remove any unreacted HCl gas. Themixture was concentrated at 45° C. in vacuo. The mixture was partitionedbetween methylene chloride (300 mL) and water (400 mL). The organiclayer was separated, dried over anhydrous magnesium sulfate, andconcentrated. The concentrate was dissolved in 200 mL of warm hexane,filtered and allowed to cool to room temperature. The title compound(9.1 g) was collected by filtration.

Reference example 13 2,4-dichloroquinazoline ##STR80##

A mixture of benzoyleneurea (20.0 g), phosphorus oxychloride (100 mL)and N,N-dimethylaniline (12 mL) was refluxed for five hours. Afterstirring overnight at room temperature, the mixture was heated to refluxonce more for an additional four hours. The cooled mixture was thenpoured into ice and the precipitate collected. The precipitate waspurified on silica gel column with 5% methanol/chloroform as eluent. Theisolated product was triturated in ether/hexane and collected to obtainthe title compound (6.9 g ).

The following compound was obtained by the same procedure as Referenceexample 13, by using 6-chloro-(1H,3H)-quinazolin-2,4-dione prepared byReference example 11.

Reference example 13(a) 2,4,6-trichloroquinazoline ##STR81##

mp: 125° C. NMR (200 MHz, DMSO-d6): δ 8.09 (d, 1H), 8.21 (dd, 1H), 8.33(d, 1H).

Reference example 14 4-phenylmethylamino-2-chloroquinazoline ##STR82##

The title compound having the following physical data, was obtained bythe same procedure as Example 1, by using the dichloroquinazolineprepared in Reference example 13 and phenylmethylamine (equivalent todichloroquinazoline).

mp: 178°-180° C. NMR (CDCl₃): δ 4.86 (d, 2H), 6.05 (s, 1H), 7.32-7.51(m, 6H), 7.62-7.85 (m, 3H).

The following compounds were obtained by the same procedure as Referenceexample 14, by using the corresponding 4-chloro compounds prepared inReference example 13(a) and 12, respectively.

Reference example 14(a) 4-phenylmethylamino-2,6-dichloroquinazoline##STR83##

NMR (200 MHz, DMSO-d6): δ 4.74 (d, 2H), 7.28-7.43 (m, 5H), 7.67 (d, 1H),7.85 (dd, 1H), 8.50 (d, 1H), 9.36 (broad, 1H).

Reference example 14(b) 4-phenylmethylamino-2-chloromethylquinazoline##STR84##

mp: 137°-139° C. NMR (CDCl₃): δ 4.68 (s, 2H), 4.90 (d, 2H), 6.00 (bs,1H), 7.27-7.90 (m, 9H).

EXAMPLE 5 4-phenylmethylamino-2-(1-imidazolyl)quinazoline ##STR85##

A mixture of the 2-chloro compound (0.81 g, prepared in Referenceexample 14), imidazole (0.81 g) and phenol (3.0 g) was heated to refluxfor four and one-half hours. The mixture was then taken up inchloroform, washed twice with sodium hydroxide solution, dried overanhydrous potassium carbonate and concentrated. The concentrate wastriturated in ether and collected to obtain the title compound (0.7 g)as a yellow solid having the following physical data.

mp: 21 2°-21 4° C. NMR (CDCl₃): ,5 4.86 (d, 2H), 6.05 (broad s, 1H),7.32-7.51 (m, 6H), 7.62-7.85 (m, 3H).

The following compounds were obtained by the same procedure as Example5, by using 4-phenylmethylamino-2-chloroquinazoline prepared inReference example 14, 14(a) and 14(b) or corresponding quinazoline, andthe proper heterocyclic compounds.

EXAMPLE 5(a) 4-phenylmethylamino-2-(2-methyl-1-imidazolyl)quinazoline##STR86##

mp: 182°-186° C. NMR (CDCl₃): δ2.89 (s, 3H), 4.92 (d, 2H), 6.30 (broad,1H), 6.97 (s, 1H), 7.30-7.50 (m, 5H), 7.73-7.82 (m, 3H), 7.96 (s, 1H).IR (KBr): ν 3240 (w), 3060 (w), 1618 (m), 1595 (s), 1559 (s), 1439 (m),1403 (s), 1380 (s), 1305 (s), 766 (w), 696 (w)cm⁻¹.

EXAMPLE 5(b) 4-phenylmethylamino-2-(1,2,4-triazol-1-yl)quinazoline##STR87##

mp: 193°-195° C. NMR (CDCl₃): ,5 4.73 (d, 2H), 6.02 (bs, 1H), 7.17-7.74(m, 8H), 7.59-7.65 (m, 3H). IR (KBr): ν 3240 (w), 3125 (w), 1618 (m),1596 (s), 1580 (s), 1547 (s), 1491 (m), 1384 (s), 1314 (s), 1207 (s),1052 (w), 763 (m), 698 (m)cm⁻¹.

EXAMPLE 5(c) 4-phenylmethylamino-6-chloro-2-(1-imidazolyl)quinazoline##STR88##

mp: 260°-264° C. (dec.). NMR (200 MHz, DMSO-d6): δ 4.84 (d, 2H), 7.09(s, 1H), 7.28-7.50 (m, 5H), 7.70 (d, 1H), 7.82 (dd, 1H), 7.93 (s, 1H),8.52 (d, 1H), 8.56 (s, 1H), 9.40 (broad. 1H).

EXAMPLE 5(d) 4-phenylmethylamino-2-((1-imidazolyl)methyl)quinazoline##STR89##

mp: 174°-176° C. NMR (200 MHz, DMSO-d6): ,5 4.70 (d, 2H), 5.18 (s, 2H),6.88 (s, 1H), 7.16 (s, 1H), 7.17-7.40 (m, 4H), 7.50 (m, 1H), 7.60-7.82(m, 3H), 8.28 (d, 1H), 8.92 (m, 1H).

EXAMPLE 5(e)6-ethoxycarbonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazoline##STR90##

mp: 193° C. (dec.) NMR (200 MHz, CDCl₃) δ: 1.58 (t, 3H), 4.69-4.80(m,4H), 6.62 (br, 1H), 7.17 (s, 1H), 7.35-7.44 (m, 5H), 7.89 (d, 1H), 7.98(s, 1H), 8.24 (dd, 1H), 8.58 (d, 1H), 8.67 (s, 1H). IR (KBr)ν: 3275,1652, 1626, 1588, 1472, 1438, 1314, 1093, 1055, 1014 cm⁻¹.

EXAMPLE 6 4-phenylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR91##

The title compound having the following physical data, was obtained bythe same procedure as Example 2, by using the free base prepared inExample 5 and HCl/methanol solution.

mp: 248°-250° C. NMR (200 MHz, DMSO-d6): δ 4.96 (d, 2H), 7.20-7.40 (m,3H), 7.50-7.54 (m, 2H), 7.63 (t, 1H), 7.75-7.81 (m, 1H), 7.88-7.90 (m,2H), 8.43 (s, 1H), 8.55 (d, 1H), 9.85 (broad t, 1H), 10.03 (s, 1H). IR(KBr): ν 3055 (broad), 2655 (broad), 1634 (s), 1569 (s), 1520 (m), 1472(m), 1395 (s), 760 (w) cm⁻¹.

By the same procedure as described in Reference example 13 and 14 andExample 5 and 6, the below compounds having the following physical datawere given.

EXAMPLE 6(a) 4-phenylmethylamino-6-chloro-2-(1-imidazolyl)quinazolinedihydrochloride ##STR92##

mp: 1 86° C. (dec.). NMR (200 MHz, DMSO-d6): δ 4.95 (m, 2H), 7.25-7.40(m, 3H), 7.49-7.53 (m, 2H), 7.78 (d, 1H), 7.90 (t, 1H), 7.92 (dd, 1H),8.43 (t, 1H), 8.71 (d, 1H), 9.88 (broad, 1H), 10.03 (t, 1H).

EXAMPLE 6(b) 4-phenylmethylamino-2-((1-imidazolyl)methyl)quinazolinedihydrochloride ##STR93##

mp: 306° C.(dec.). NMR (200 MHz, DMSO-d6): δ 4.64 (m, 2H), 5.81 (s, 2H),7.17-7.40 (m, 5H), 7.68-8.10 (m, 5H), 8.68 (m, 1H), 9.26 (s, 1H).

The following compound was obtained by the same procedure as describedin Reference example 13, 14 and example 5 and 6, by using thecorresponding (1H,3H)-quinazoline-2,4-dione or its derivative andcorresponding amine.

EXAMPLE 6(c) 6-bromo-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR94##

mp:199°-202° C., (dec.) NMR (200 MHz, DMSO-d6) δ: 4.95 (m, 2H),7.25-7.40 (m, 3H), 7.49-7.53 (m, 2H), 7.70 (d, 1H), 7.81 (t, 1H), 8.01(dt, 1H), 8.38 (d, 1H), 8.81 (d, 1H), 9.80 (broad, 1H), 9.88 (d, 1H).

EXAMPLE 6(d) 7-chloro-4-phenylmethylamino-2-(1-imidazolyl)quinazoline##STR95##

mp: 265°-268° C. NMR (200 MHz, DMSO-d6):8 4.85 (s, 2H), 7.08 (s, 1H),7.21-7.40 (m, 3H), 7.42-7.58 (m, 2H), 7.71 (s, 1H), 7.91 (s, 1H), 8.35(d, 1H), 8.54 (s, 1H). IR (KBr): ν 3260 (w), 3135 (w), 1609 (s), 1570(s), 1473 (s), 1451 (s), 1418 (s), 1349 (m), 1307 (m), 1037 (m), 778(w), 698 (w) cm⁻¹.

EXAMPLE 6(e)6-chloro-4-phenylmethylamino-2-(1-imidazolylmethyl)quinazolinedihydrochloride ##STR96##

mp: 290° C., (dec.) NMR (200 MHz, DMSO-d6)8:4.66 (d, 2H), 5.72 (s, 2H),7.18-7.42 (m, 5H), 7.72-8.05 (m, 4H), 8.76 (s, 1H), 9.27 (s, 1H).

EXAMPLE 6(f) 6-nitro-4-phenylmethylamino-2-(1-imidazolyl)quinazolinehydrochloride ##STR97##

mp: 190° C., (dec.) NMR (200 MHz, DMSO-d6) δ: 5.00 (m, 2H), 7.25-7.42(m, 3H), 7.45-7.53 (m, 2H), 7.76 (broad, 1H), 7.87-7.93 (d, 1H), 8.39(broad, 1H), 8.57-8.65 (d, 1H) 9.56 (s, 1H), 9.82 (broad, 1H), 10.28(broad, 1H). IR (KBr)ν: 1335(s), 1403(s), 1438(w), 1518(w), 1601(s),3405(broad), 3445(w) cm⁻¹.

EXAMPLE 6(g) 6-methoxy-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR98##

mp: 196° C., (dec.) NMR (200 MHz, DMSO-d6) 8:3.93 (s,3H), 4.98 (m, 2H),7.25-7.42 (m, 3H), 7.45-7.57 (m, 2H), 7.74 (d, 1H), 7.87 (d, 1H), 7.95(d, 1H), 8.41 (d, 1H), 9.55 (broad, 1H), 9.96 (d, 1 H). IR (KBr)ν:1254(m), 1395(s), 1506(m), 1558(s), 1601(s), 3065(w), 3245(w), and3395(w) cm⁻¹.

EXAMPLE 6(h) 6-chloro-4-phenylamino-2-(1-imidazolylmethyl)quinazolinedihydrochloride ##STR99##

mp: 280° C., (dec.) NMR (200 MHz, DMSO-d6) 67 : 5.72 (s, 2H), 7.12-8.03(m, 9H), 8.99 (m, 1H), 9.26 (s, 1H), 10.65 (bs, 1H). IR (KBr) ν: 3100(m), 2830 (m), 2565 (m), 1635 (m), 1608 (m), 1578 (sd), 1492 (ms), 1151(m) cm⁻¹.

EXAMPLE 6(i)6-chloro-4-(3-carboxyphenyl)amino-2-(1-imidazolylmethyl)quinazolinedihydrochloride ##STR100##

mp: 285 PC, (dec.) NMR (200 MHz, DMSO-d6) δ: 5.69 (s, 2H), 7.49 (t, 1H),7.70-8.02 (m, 6H), 8.26 (m, 1H), 8.90 (m, 1H), 9.26 (s, 1H), 10.50 (bs,1H). IR (KBr)ν: 3326 (m), 3065 (m), 2835 (m), 1698 (m), 1631 (m), 1602(m), 1561 (s), 1486 (m), 1444 (m), 1400 (m), 1376 (mw) cm⁻¹.

EXAMPLE 6(j)6-dimethylaminosulfonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazolinehydrochloride ##STR101##

mp: 264°-266° C. NMR (200 MHz, DMSO-d6) 8: 2.69(s, 6H), 5.00(d, 2H),7.25-7.45(m, 3H), 7.46-7.54(m, 2H), 7.78(m, 1H), 7.93(dd, 1H), 8.13(d,1H), 8.40(m, 1H), 8.95(m, 1H), 9.84(m, 1H), 10.13(br, 1H). IR (KBr):δ3400(m), 3320(m), 2960(w), 1597(s), 1556(m), 1520(m), 1445(m), 1398(s),1341(s), 1164(s), 728(s), 579(s)cm⁻¹.

EXAMPLE 6(k) 4-(2-furylmethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR102##

mp: 230° C., (dec.) NMR (200 MHz, DMSO-d6)8:4.99 (d, 2H), 6.48 (m, 2H),7.57-7.97 (m, 5H), 8.49 (m, 2H), 9.64 (t, 1H), 10.08 (s, 1H).

EXAMPLE 6(I) 4-(2-thienylmethyl)amino-2-(1-imidazolyl)quinazoline##STR103##

mp: 234°-235° C. NMR (200 MHz, DMSO-d6): δ 5.03 (d, 2H), 7.00 (m, 1H),7.13 (s, 1H), 7.18 (d, 1H), 7.37 (d, 1H), 7.52 (t, 1H), 7.78 (m, 2H),8.02 (s, 1H), 8.28 (d, 1H), 8.67 (s, 1H), 9.40 (t, 1H). IR (KBr): ν 3255(w, broad), 1617 (w), 1668 (s), 1470 (s), 1402 (s), 1321 (m) cm⁻¹.

EXAMPLE 6(m)4-(2-tetrahydrofuranylmethyl)amino-2-(1-imidazolyl)quinazoline##STR104##

mp: 98°-150° C. NMR (200 MHz, DMSO-d6)8:1.62-2.13 (m, 4H), 3.62-3.90 (m,4H), 4,12-4.31 (m, 2H), 7.54-7.97 (m, 4H), 8.44 (s, 1H), 9.32 (t, 1H),10.02 (s, 1H). IR (KBr) ν: 3500-2700 (s, broad), 1635 (m), 1576 (m),1396 (m), 1063 (w), 765 (w) cm⁻¹.

EXAMPLE 6(n) 4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR105##

mp: 210°-215° C. NMR (200 MHz, DMSO-d6) δ: 3.31 (s, 3H), 3.66 (t, 2H),3.85 (q, 2H), 7.61 (t, 1H), 7.78 (d, 1H), 7.85 (m, 1H), 8.42 (m, 2H),9.23 (t, 1H), 9.95 (s, 1H).

EXAMPLE 6(o)4-phenylmethylamino-2-(1-imidazolyl)-5,6,7,8-tetrahydro-quinazolinedihydrochloride ##STR106##

mp: 195° C., (dec.) NMR (200 MHz, DMSO-d6)8:1.79 (m, 4H), 2.45 (m, 2H),2.66 (m, 2H), 4.74 (d, 2H), 7.17-7.48 (m, 5H), 7.83 (cs, 1H), 8.13 (t,1H), 8.24 (cs, 1H), 9.84 (cs, 1H).

EXAMPLE 6(p)6-dimethylaminomethylideneaminosulfonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR107##

mp: 225° C. NMR (200 MHz, DMSO-d6) δ: 2.93 (s, 3H), 3.18 (s, 3H), 4.97(d, 2H), 7.25-7.40 (m, 3H), 7.49-7.53 (m, 2H), 7.79 (s, 1H), 7.84 (d,1H), 8.15 (dt, 1H), 8.30 (s, 1H), 8.39 (s, 1H), 9.00 (s, 1H), 9.86 (s,1H), 10.10 (t, 1H).

EXAMPLE 6(q)6-(phenylmethylaminosulfonyl)-4-phenylmethylamino-2-(1-imidazolyl)quinazoline##STR108##

mp: 207°-8° C. NMR (200 MHz, DMSO-d6) δ: 4.09 (d, 2H), 4.89 (m, 2H),7.11 (s, 1H), 7.16-7.52 (m, 10H), 7.79 (d, 1H), 7.96 (d, 1H), 8.07 (dd,1H), 8.28 (t, 1H), 8.60 (s, 1H), 8.83 (m, 1H), 9.80 (broad t, 1H).

EXAMPLE 6(r) 4-(2-phenylethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR109##

mp: 70°-100° C. NMR (200 MHz, DMSO-d6) δ: 3.05 (t, 2H), 3.95 (q, 2H),7.12-7.38 (m, 6H), 7.57 (t, 1H), 7.73 (m, 2H), 7.89 (m, 3H), 8.41 (m,2H), 9.38 (t, 1H), 9.96 (s, 1H).

EXAMPLE 6(s) 4-cyclohexylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR110##

mp: 140°-150° C. NMR (200 MHz, DMSO-d6)8:0.98-1.32 (m, 5H), 1.53-1.90(m, 6H), 3.58 (t, 2H), 7.59 (t, 1H), 7.77 (m, 1H), 7.89 (t, 2H), 8.41(s, 1H), 8.56 (d, 1H), 9.28 (t, 1H), 9.97 (s, 1H).

EXAMPLE 6(t) 6-carboxy-4-phenylmethylamino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinazoline dihydrochloride ##STR111##

mp: 105° C. (dec.) NMR (200 MHz, DMSO-d6) 8:1.82 (m, 1H), 2.10 (m, 1H),2.71 (m, 5H), 4.74 (d, 2H), 7.18-7.47 (m, 5H), 7.82 (s, 1H), 8.24 (s,1H), 8.25 (m, 1H), 9.84 (s, 1H). IR (KBr)ν: 3140 (bin), 2935 (bin), 1718(mw), 1654 (m), 1617 (ms), 1522 (mw), 1394 (m) cm⁻¹.

EXAMPLE 6(u)6-phenylmethylaminocarbonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR112##

mp: 235°-237° C. NMR (200 MHz, DMSO-d6) δ: 4.54 (d, 2H), 7.20-7.40 (m,8H), 7.48-7.52 (m, 2H), 7.70 (s, 1H), 7.81 (d, 1H), 8.31 (dd, 1H), 8.37(s, 1H), 9.09 (s, 1H), 9.22 (br, 1H), 9.82 (s, 1H), 9.89 (br, 1H). IR(KBr) ν: 3500-3000 (br), 1647, 1604, 1555, 1453, 1398, 1 31 5, 699 cm⁻¹.

EXAMPLE 6(v)4-(4-tetrahdyropyranylmethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR113##

mp: 160°-195° C. NMR (200 MHz, DMSO-d6) δ: 10.0 (m, 1H), 9.29 (m, 1H),8.53 (d, 1H), 8.45 (m, 1H), 7.82-7.95 (d, 2H), 7.75 (d, 1H), 7.60 (t,1H), 3.86 (m, 2H), 3.64 (m, 2H) 3.28 (t, 2H), 2.02 (m, 1H), 1.60-1.75(m, 2H), 1.21-1.48 (m, 2H). IR (KBr)ν: 1635, 1604, 1562, 1524, 1471,1443, 1393, 1091, 762 cm⁻¹.

EXAMPLE 6(w)6-methoxy-4-(4-tetrahydropyranylmethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR114##

mp: 170°-190° C. NMR (200 MHz, DMSO-d6) δ: 9.96 (s, 1H), 9.15 (m, 1H),9.42 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.71 (d, 1H), 7.52 (dd, 1H),3.94 (s, 3H), 3.80-3.95 (m, 2H), 3.62 (m, 2H), 3.29 (t, 2H), 2.02 (m,1H), 1.60-1.75 (m, 2H), 1.20-1.49 (m, 2H). IR (KBr)ν: 1637, 1605, 1569,1524, 1473, 1440, 1391, 1251, 1091, 1020 cm⁻¹.

EXAMPLE 6(x)6-chloro-4-(4-tetrahydropyranylmethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR115##

mp: 155°-185° C. NMR (200 MHz, DMSO-d6) 8:9.89 (s, 1H), 9.25 (m, 1H),8.66 (m, 1H), 8.41 (m, 1H), 7.72-7.96 (m, 3H), 3.81-3.95 (m, 2H),3.56-3.70 (m, 2H), 3.28 (t, 2H), 2.02 (m, 1H), 1.63-1.79 (m, 2H),1.20-1.46 (m, 2H). IR (KBr)ν: 1604, 1577, 1524, 1497, 1446, 1396, 1349,1089 cm⁻¹.

EXAMPLE 6(y) 6-iodo-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR116##

mp: 183° C., (dec.) NMR (200 MHz, DMSO-d6) δ: 4.95 (m, 2H), 7.25-7.40(m, 3H), 7.45-7.60 (m, 3H), 7.88 (t, 1H), 8.16 (dt, 1H), 8.43 (t, 1H),8.93 (s, 1H), 9.78 (t, 1H), 10.01 (d, 1H). IR (KBr) ν: 3060, 2685, 1634,1600, 1541, 1406, 1390 cm⁻¹.

EXAMPLE 6(z)4-(4-trifuloromethoxyphenylmethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR117##

mp: 140°-145° C. NMR (200 MHz, DMSO-d6) δ: 5.01 (m, 2H), 7.30-7.40 (m,2H), 7.60-7.88 (m, 6H), 8.42-8.55 (m, 2H), 9.78 (bm, 1H), 10.35 (s, 1H).IR (KBr)ν: 3070, 1634, 1604, 1560, 1525, 1394, 1263, 1224, 1164 cm⁻¹.

EXAMPLE 6(aa)4-(3-trifluoromethoxyphenylmethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR118##

(2HCl salt)

mp: 170°-180° C. NMR (200 MHz, DMSO-d6): 85.01(d, 2H), 7.25(d, 1H),7.42-7.71(m, 3H), 7.81 (s, 1H), 7.88(m, 2H), 8.44(s, 1H), 8.54(d, 1H),9.95(t, 1H), 10.06(s, 1H). IR(KBr): ν 3430(w), 3020(w), 2960(w),1653(s), 1603(s), 1542(m), 1396(s), 1270(s), 1216(m) cm⁻¹.

EXAMPLE 6(bb)6-methoxy-4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR119##

(2HCl salt)

mp:167.5°-170° C. NMR (200 MHz, DMSO-d6): δ 3.51 (s, 4H), 3.75-3.78(m,2H), 3.85-3.90(m, 2H), 3.93(s, 3H), 7.49(dd, 1H), 7.70(d, 1H), 7.84(t,1H), 7.98(m, 1H), 8.39(m, 1H), 9.19(br, 1H), 9.90(t, 1H). IR(KBr): ν3270(s), 2940(m), 1610(s), 1557(m), 1513(s), 1396(s), 1247(m), 1115(m),1029(w) cm⁻¹.

EXAMPLE 6(cc)4-(2-methoxyethyl)amino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinazolinedihydrochloride ##STR120##

(2HCl salt)

mp: 140°-142.5° C. NMR (200 MHz, DMSO-d6): δ 1.77(s, 4H), 2.38(s, 2H),2.65(s, 2H), 3.28(s, 3H), 3.54(t, 3H), 3.57(d, 2H), 7.49(br, 1H),7.84(s, 1H), 8.30(s, 1H), 9.86(s, 1H). IR(KBr): ν 3230-2355(br, m),1555(s), 1506(s), 1526(s), 1449(w), 1395(s), 1101(m), 828(w),756(m)cm⁻¹.

EXAMPLE 6(dd) 4-(2-methoxyethyl)amino-6-iodo-2-(1-imidazolyl)quinazolinedihydrochloride ##STR121##

(2HCl salt)

mp: 159°-161° C. NMR (200 MHz, DMSO-d6): δ 3.31 (s, 3H), 3.67(t, 2H),3.88(t, 2H), 7.54(d, 1H), 7.85(t, 1H), 8.13(dd, 1H), 8.42(t, 1H),8.89(d, 1H), 9.20(t, 1H), 9.94(t, 1H). IR(KBr): ν 3205-2365(m, br),1633(s), 1604(s), 1 564(s), 1541 (s), 1506(s), 1459(m), 1409(s),1367(s), 1193(w), 1114(m), 1011(m), 859(w), 833(m), 777(m), 713(w),621(w), 526(w)cm⁻¹.

EXAMPLE 6(ee) 4-phenylmethylamino-6,8-diiodo-2-(1-imidazolyl)quinazolinedihydrochloride ##STR122##

(2HCl salt)

mp:303°-304° C. (dec.) NMR (200 MHz, DMSO-d6): δ 4.94(d, 2H), 7.33(dd,3H), 7.49(dd, 2H), 7.74(t, 1H), 8.24(t, 1H), 8.67(t, 1H), 8.88(d, 1H),9.66(s, 1H), 9.77(br, 1 H) . IR(KBr): ν 3410-2365(br, m), 1599(s),1437(m), 1387(s), 1350(m), 1314(m), 1273(w), 1061(w), 1020(w), 793(w),748(w), 701(w), 620(w)cm⁻¹.

EXAMPLE 6(ff)4-(2-methaxyethyl)amino-6-methoxy-2-(2-methyl-1-imidazolyl)quinazolinedihydrochloride ##STR123##

(2HCl salt)

mp: 263°-264° C. NMR (200 MHz, DMSO-d6): δ 3.04(s, 3H), 3.31(s, 3H),3.68(m, 2H), 3.84(m, 2H), 3.92(s, 3H), 7.50(dd, 2H), 7.72(m, 2H),7.91(s, 1H), 8.30(s, 1H), 9.10(m, 1H). IR(KBr): ν 3230(w), 2680(w),1615(s), 1592(s), 1560(s), 1420(m), 1382(m), 1248(m), 909(w) cm⁻¹.

EXAMPLE 6(gg) 4-(2-hydroxyethyl)amino-6-methoxy-2-(1-imidazolyl)quinazoline dihydrochloride ##STR124##

(2HCl salt)

mp: 228°-233° C. NMR (200 MHz, D20): δ 3.63(t, 2H), 3.74(s, 3H), 3.83(t,2H), 6.90(d, 1H), 7.16(dd, 1H), 7.26(d, 1H), 7.57(d, 1H), 7.96(d, 1H),9.23(s, 1H). IR(KBr): ν 2700-3400(br), 1605(s), 1569(m), 1520(m),1394(m), 1246(w), 1040(w), 81 5(w) cm⁻¹.

EXAMPLE 6(hh)4-(2-methoxyethyl)amino-6,8-diiodo-2-(1-imidazolyl)quinazolinedihydrochloride ##STR125##

(2HCl salt)

mp: 244°-246.5° C. NMR (200 MHz, DMSO-d6): δ 3.31(3H), 3.65(2H),3.89(2H), 7.79(s, 1H), 8.29(s, 1H), 8.68(s, 1H), 8.89(s, 1H), 9.32(br,1H). IR(KBr): ν 3240-2335(br, m), 1598(s), 1553(w), 1523(w), 1476(m),1436(m), 1383(m), 1354(m), 1275(w), 1107(w), 1086(m), 1018(m), 991(w),860(w), 793 (m), 752(w), 724(w), 615(w)cm⁻¹.

EXAMPLE 6(ii)4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinazolinedihydrochloride ##STR126##

(2HCl salt)

mp: 125°-128° C. NMR (200 MHz, DMSO-d6): δ 1.80(4H), 2.40(2H), 3.65(br,8H), 7.45(br, 1H), 7.85(d, 1H), 8.30(d, 1H), 9.85(d, 1H). IR(KBr): ν3380(s), 3120(s), 2945(m), 2755-2460(m), 1615(s), 1540(s), 1457(m),1428(m), 1390(s), 1350(m), 1319(w), 1103(m), 1070(m), 829(w), 624 (w)cm⁻¹.

EXAMPLE 6(jj)4-(2-phenoxyethyl)amino-6-methoxy-2-(1-imidazolyl)quinazoline and itsdihydrochloride ##STR127##

(free base)

mp: 213°-21 4° C. NMR (200 MHz, DMSO-d6): δ 3.89 (s, 3H), 4.04(d, 2H),4.31(t, 2H), 6.93-7.01 (3H), 7.08(d, 1H), 7.28(td, 2H), 7.45(dd, 1H),7.64(d, 1H), 7.78(d, 1H), 7.93(t, 1H), 8.57(s, 1H), 9.85(br, 1H).IR(KBr): ν 1599(s), 1555(s), 1491(s), 1409(s), 1382(w), 1310(m),1242(s), 1051 (s), 752(w) cm⁻¹.

(2HCl salt)

mp: 184°-186° C. NMR (200 MHz, DMSO-d6): δ 3.94(s, 3H), 4.12(d, 2H),4.33(t, 2H), 6.90-7.01 (3H), 7.29(t, 2H), 7.53(dd, 1H), 7.88(t, 1H),7.96(d, 1H), 8.40(t, 1H), 9.31 (br, 1H), 9.93(d, 1H). IR(KBr): ν3050(m), 2840-2335(m), 1637(s), 1598(s), 1497(m), 1472(m), 1380(s),1258(s), 1122(w), 1077(w), 1029(m), 775(m), 747(m)cm⁻¹.

EXAMPLE 6(kk)4-(2-(2-hydroxyethoxy)ethyl)amino-6-iodo-2-(1-imidazolyl)quinazoline andits dihydrochloride ##STR128##

(free base)

NMR (200 MHz, DMSO-d6): δ 3.50(s, 4H), 3.75(dd, 2H), 3.78(d, 2H),4.59(br, 1H), 7.10(d, 1H), 7.47(dd, 1H), 7.95(d, 1H), 8.05(d, 1H),8.52(d, 1H), 8.7 (s, 1H), 8.57(br, 1H).

(2HCl salt)

mp: 132°-135° C. NMR (200 MHz, DMSO-d6): δ 3.50(s, 4H), 3.75(d, 2H),3.86(d, 2H), 7.53(d, 1H), 7.83(s, 1H), 8.15(dd, 1H), 8.40(s, 1H),8.89(d, 1H), 9.22(br, 1H), 9.90(s, IR(KBr): ν 3230-2720(br, m), 1607(s),1555(m), 1526(m), 1492(m), 1445(m), 1394(s), 1348(m), 1118(m), 1063(m),1027(m), 859(m), 622 cm⁻¹.

EXAMPLE 6(11)4-(2-methoxyethyl)amino-6-methylthio-2-(1-imidazolyl)quinazoline and itsdihydrochloride ##STR129##

(free base)

mp: 201°-202° C. NMR (200 MHz, DMSO-d6): δ 2.61(s, 3H), 3.32(s, 3H),3.65(m, 2H), 3.81(m, 2H), 7.10(s, 1H), 7.58-7.73(m, 2H), 7.95(s, 1H),8.10(s, 1H), 8.59(s, 1H), 8.83 (t, 1H).

(2HCl salt)

mp: 230°-232° C. NMR (200 MHz, DMSO-d6): δ 2.65(s, 3H), 3.31(s, 3H),3.66(m, 2H), 3.88(m, 2H), 7.64-7.83(m, 2H), 7.89(s, 1H), 8.24(m, 1H),8.42(s, 1H), 9.28(t, 1H), 9.98(s, 1H).

EXAMPLE 6(mm)4-(2-(2-hydroxyethoxy)ethyl)amino-6-methylthio-2-(1-imidazolyl)quinazoline##STR130##

(free base)

mp: 169°-172° C.

NMR (200 MHz, DMSO-d6): δ 2.61(s, 3H), 3.51(s, 4H), 3.76(m, 4H), 4.60(m,1H), 7.10(s, 1H), 7.57-7.76(m, 2H), 7.95(s, 1H), 8.09(s, 1H), 8.59(s,1H), 8.82(m, 1H).

EXAMPLE 6(nn)4-(2-(2-hydroxyethoxy)ethyl)amino-6-methylthio-2-(1-imidazolyl)quinazolinedihydrochloride ##STR131##

(2HCl salt)

mp: 180°-182° C. NMR (200 MHz, DMSO-d6): δ 2.65(s, 3H), 3.51(s, 4H),3.75(m, 2H), 3.90(m, 2H), 7.64-7.82(m, 2H), 7.87(m, 1H), a.26(m, 1H),8.42(1H), 9.34(t, 1H), 9.98 (m, 1H).

EXAMPLE 6(oo)6-methylthio-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR132##

mp: 192°-195° C. NMR (200 MHz, DMSO-d6): δ 2.64(s, 3H), 4.96(d, 2H),7.31-7.86(m, 9H), 8.26(s, 1H), 8.40(s, 1H), 9.75(t, 1H), 9.96(s, 1H). IR(KBr): ν 3210(w), 3040(m), 2600(m), 1630(s), 1556(s), 1495(m), 1433(m),1510(s), 1339(m), 1203(w), 1112(w), 1091(w), 1013(w), 823(w), 743(m),704(m), 615(w)cm⁻¹.

EXAMPLE 6(pp)4-(3-methoxypropyl)amino-6-methoxy-2-(1-imidazolyl)quinazolinedihydrochloride ##STR133##

mp: 191°-194° C. NMR (200 MHz, DMSO-d6): δ 1.94(m, 2H), 3.25(s, 3H),3.42(t, 2H), 3.69(m, 2H), 3.90(s, 3H), 7.45(m, 1H), 7.64(d, 1H), 7.86(m,1H), 7.99(m, 1H), 8.35(m, 1H), 9.30(m, 1H), 9.88(m, 1H). IR (KBr): ν1641, 1603, 1587, 1573, 1529, 1421, 1382, 1253, 1111, 1027, 858 cm⁻¹.

EXAMPLE 6(qq)4-(2-methoxyethyl)amino-6-methoxycarbonyl-2-(1-imidazolyl)quinazoline##STR134##

mp: 252°-253° C. NMR (200 MHz, DMSO-d6): δ 3.32(s, 3H), 3.66(t, 2H),3.83(t, 2H), 3.92(s, 3H), 7.13(s, 1H), 7.75(d, 1H), 7.98(s, 1H), 8.23(s,1H), 8.63(s, 1H), 9.02(s, 1H), 9.28. IR (KBr):δ 3245(w), 3140(w),2900(w), 1724(s), 1601(s), 1473(s), 1437(s), 1407(s), 1310(s), 1119(m),1021(m), 766cm⁻¹.

EXAMPLE 6(rr)4-[2-(2-hydroxyethoxy)ethyl]amino-6-methoxycarbonyl-2-(1-imidazolyl)quinazoline##STR135##

mp: 233°-235° C. NMR (200 MHz, DMSO-d6): δ 3.50(m, 4H), 3.70-3.90(m,4H), 3.93(s, 3H), 4.60(m, 1H), 7.12(s, 1H), 7.75(d, 1H), 7.99(s, 1H),8.25(dd, 1H), 8.63(s, 1H), 9.03(m, 1H), 9.28(m, 1H). IR (KBr):δ3245(mw), 2950(w), 1730(ms), 1626(w), 1603(s), 1558(m), 1474(m),1437(m), 1406(m), 1309(m), 1281(w), 1229(w), 1125(w), 1102(w), 1051 (w)cm⁻¹.

EXAMPLE 6(ss)4-(2-methylthioethyl)amino-6-methoxy-2-(1-imidazolyl)quinazoline##STR136##

mp: 168°-178° C. NMR (200 MHz, DMSO-d6): δ 2.17(s, 3H), 2.89(t, 2H),3.90(m, 2H), 3.93(s, 3H), 7.55(dd, 1H), 7.69(d, 1H), 7.87(s, 1H),7.97(s, 1H), 8.40(s, 1H), 9.34(t, 1H), 9.93(s, 1H). IR (KBr) :v 3410,3095, 2675, 1635, 1609, 1587, 1400, 1264, 1018 cm⁻¹

EXAMPLE 6(tt)4-(2-methylsulfinylethyl)amino-6-methoxy-2-(1-imidazolyl)quinazoline##STR137##

mp: 238°-242° C. NMR (200 MHz, DMSO-d6): δ 2.63(s, 3H), 3.10-3.70(m,4H), 3.92(s, 3H), 7.53(dd, 1H), 7.72(d, 1H), 7.88(d, 2H), 8.48(s, 1H),9.43(m, 1H), 10.01 (s, 1H). IR (KBr):n 3435, 3005, 2710, 1625, 1560,1398, 1248, 1020, 825 cm⁻¹.

EXAMPLE 6(uu)4-(2-methylsulfonylethyl)amino-6-methoxy-2-(1-imidazolyl)quinazoline##STR138##

mp: 245°-252° C. NMR (200 MHz, DMSO-d6): δ 3.09(s, 3H), 3.61 (t, 2H),3.92(s, 3H), 4.09(m, 2H), 7.54(dd, 1H), 7.76(d, 1H), 7.88(s, 2H),8.45(s, 1H), 9.38(br, 1H), 9.89(s, 1H).

Reference example 15 2-(2-(3-pyridyl)vinyl)quinazolin-4-one ##STR139##

A mixture of 2-methylquinazolin-4-one (6.1 g) and 3-pyridinecarbaldehyde(4.1 g) in acetic acid (80 mL) was heated to reflux for 20 hours. Aftercooling to room temperature, the precipitate was collected byfiltration, washed with methanol and dried to obtain the title compoundas an acetic acid salt (10.5 g).

Reference example 16 4-chloro-2-(2-(3-pyridyl)vinyl)quinazoline##STR140##

A suspension of the quinazolinone compound (2.9 g, prepared in Referenceexample 15) in thionyl chloride (25 mL) and a few drops ofdimethylformamide was heated at reflux for three hours. The mixture wasthen concentrated, the concentrate poured into 150 mL portions ofchloroform, dried over potassium carbonate and concentrated to obtainthe title compound (1.1 g) as a red oil.

EXAMPLE 7 4-phenylmethylamino-2-(2-(3-pyridyl)vinyl)quinazoline##STR141##

The title compound having the following physical data, was obtained bythe same procedure as Example 1, by using the 4-chloro compound preparedin Reference example 16 and phenylmethylamine. The product was purifiedby column chromatography.

mp: 178°-179° C. NMR (CDCl₃): δ 4.96 (d, 2H), 6.11 (broad, 1H),7.30-7.55 (m, 8H), 7.70-7.81 (m, 2H), 7.99 (d, 1H), 8.34 (s, 1H),8.36-8.45 (m, 1H), 8.55-8.58 (dd, 1H), 8.90-8.91 (d, 1H). IR (KBr): ν3300 (m), 1577 (s), 1528 (s), 1434 (m), 1378 (s), 763 (m), 699 (m) cm⁻¹.

EXAMPLE 86-ethoxycarbonyl-4-phenylmethylamino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinazolineand its salt ##STR142##

To 349 mg (1.0 mmol) of a compound prepared in example 6(t) dissolved in20 mL of tetrahydrofuran was added 0.4 mL of thionyl chloride.Initially, a white precipitate formed, but gradually all dissolved.After stirring for 15 minutes, 20 mL of ethanol was added. Afterstirring an additional 15 minutes, the mixture was concentrated, theconcentrate triturated in ether and collected. The solid was found to bevery hygroscopic, was taken up in chloroform, treated with potassiumcarbonate solution, separated, dried over anhydrous magnesium sulfateand concentrated. Obtained 278 mg (0.7 mmol, 73% yield) of the desiredproduct as a white solid (free base).

(free base)

mp: 196°-198° C. NMR (DMSO-_(d6)): δ 1.30 (t, 3H), 1.90 (m, 1H), 2.28(m, 1H), 2.60 (m, 2H), 2.82 (m, 3H), 4,23 (q, 2H), 4.77 (d, 2H), 5.12(m, 1H), 7.10 (s, 1H), 7.37 (m, 5H), 7.83 (s, 1H), 8.54 (s, 1H). IR(KBr): 3245 (w), 1725 (ms), 1605 (s), 1532 (w), 1473 (m), 1426 (m), 1333(w) cm⁻¹.

To a suspension of 240 mg (0.64 mmol) of the compound prepared above in5 mL of ethanol was added 2 mL of ˜10% HCl in methanol. All the materialgradually dissolved. After ten minutes, the mixture was concentrated invacuo, triturated in ether and filtered to obtain 229 mg (0.51 mmol) ofthe desired product.

(2HCl salt)

mp: 158°-161° C. NMR (200 MHz, DMSO-d6)δ: 1.22 (t, 3H), 1.87(m, 1H),2.14 (m, 1H), 2.55-3.00 (m, 5H), 7.79 (s, 1H), 8.23 (s, 1H), 9.77 (s,1H). IR (KBr)ν: 3225, 1718, 1642, 1612, 1518, 1393 cm⁻¹.

EXAMPLE 8(a)6-ethylaminocarbonyl-4-phenylmethylamino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinazolinedihydrochloride ##STR143##

By the same procedure as described in example 8, by using ethylamineinstead of ethanol, the title compound having the following physicaldata was given.

mp: 147° C., (dec.)

NMR (200 MHz, DMSO-d6) δ: 1.04 (q, 3H), 1.65-2.06 (m, 2H), 2.50-2.80 (m,5H), 3.10 (m, 2H), 4.72 (m, 2H), 7.18-7.48 (m, 5H), 7.81 (s, 1H), 8.05(t, 1H), 8.18 (M, 1H), 8.24 (m, 1H), 9.82 (s, 1H). IR (KBr) ν:3265-2580, 2365, 1653, 1 61 3, 1576, 1540, 1449, 1390, 1352, 1144, 1060,750, 701,624 cm⁻¹.

EXAMPLE 9 4-phenylmethylamino-2-(1-imidazolyl)quinazolinedimethanesulfonate ##STR144##

By the same procedure as described in Reference example 13 and 14 andexample 5 and 6, by using methanesulfonic acid instead of hydrochloricacid, the title compound and the following compounds having thefollowing physical data were given.

mp: 140°-143° C. NMR (200 MHz, DMSO-d6) δ: 2.38 (s, 6H), 4.95 (m, 2H),7.20-8.00 (m, 9H), 8.40-8.53 (m, 2H), 9.64 (t, 1H), 10.00 (s, 1H).

EXAMPLE 9(a)6,7-dimethoxy-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedimethanesulfonate ##STR145##

mp: 205° C., (dec.) NMR (200 MHz, DMSO-d6) δ: 2.36 (s, 6H), 3.92 (s,3H), 3.95 (s, 3H), 4.95 (m, 2H), 7.18 (d, 1H), 7.21-7.53 (m, 5H), 7.82(s, 1H), 7.87 (m, 1H), 8.39 (m, 1H), 9.21 (t, 1H), 9.94 (m, 1H).

EXAMPLE 9(b)4-(3,4-dimethoxyphenylmethyl)amino-2-(1-imidazolyl)quinazoline 1.5methanesulfonate ##STR146##

mp: 163°-173° C. NMR (200 MHz, DMSO-d6) δ: 2.34 (s, 4H), 3.73 (d, 6H),4.88 (d, 2H), 6.02 (d, 1H), 7.03 (d, 1H), 7.16 (s, 1H), 7.62 (t, 1H),7.78 (d, 1H), 7.89 (m, 2H), 8.45 (d, 1H), 8.48 (s, 1H), 9.55 (t, 1H),10.02 (s, 1H).

EXAMPLE 9(c) 4-(2-phenoxyethyl)amino-2-(1-imidazolyl)quinazolinedimethanesulfonate ##STR147##

mp: 144°-161° C. NMR (200 MHz, DMSO-d6) δ: 2.39 (s, 6H), 4.12 (q, 2H),4.34 (t, 2H), 6.97 (m, 3H), 7.28 (t, 2H), 7.63 (m, 1H), 7.80 (s, 1H),7.89 (m, 2H), 8.45 (m, 2H), 9.30 (m, 2H), 9.97 (s, 1H). IR (KBr) ν:3700-2800 (broad), 1636 (s), 1211 (s) cm⁻¹.

EXAMPLE 106-carboxy-4-phenylmethylamino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinazolinesodium salt ##STR148##

A solution of 200 mg (0.57 mmol) of a compound prepared in example 6(t)dissolved in 25 mL of tetrahydrofuran was filtered to remove darkinsoluble material present. To the filtrate was added 0.25 mL (0.62mmol) of 2.5N sodium hydroxide solution. Some precipitate formed. Themixture was concentrated and pumped in vacuum. The concentrate wastriturated in tetrahydrofuran and ether and filtered. The solid waswashed with ether and filtered to obtain 190 mg (0.51 mmol) of thedesired product as a white solid.

mp: 240° C., (dec.) NMR (200 MHz, DMSO-d6)8:1.50-1.82 (m, 2H), 1.88-2.35(m, 2H), 2.59 (m, 3H), 4.62 (s, 2H), 6.98 (s, 1H), 7.12-7.48 (m, 5H),7.73 (s, 1H), 7.86 (m, 1H), 8.33 (s, 1H).

By the same procedure as described in example 10, the compound havingthe following physical data was given.

EXAMPLE 10(a) 6-carboxy-4-phenylmethylamino-2-(1-imidazolyl)quinazolinesodium salt ##STR149##

mp: >280° C.

NMR (200 MHz, DMSO-d6) δ: 4.48 (d, 2H), 6.99 (s, 1H), 7.25 (m, 1H), 7.33(m, 4H), 7.40 (d, 1H), 7.78 (s, 1H), 7.97 (dd, 1H), 8.46 (s, 1H), 8.57(d, 1H), 9.11 (br, 1H). IR (KBr)ν: 3500-3100 (br), 1620, 1559, 1472,1399, 1307, 1224, 1056, 699 cm⁻¹.

Reference example 174-(1,1-dimethyl-2-methoxyethyl)amino-2-chloroquinazoline ##STR150##

A mixture of 2,4-dichloroquinazoline (995 mg, 5 mmol), triethylamine(0.7 ml, 5 mmol) and 1,1-dimethyl-2-methoxyethylamine (30 mL, 0.5Mmethanol sol., 15 mmol) was stood at room temperature for 1 week. Thereaction mixture was concentrated and partitioned between ethyl acetateand water. Organic layer was washed with water and brine, dried overMgSO₄ and concentrated. The residue was purified on 50 g of silica gelcolumn eluting with 50% ethyl acetate in hexane to obtain the titlecompound (176 mg) as a white solid.

NMR (CDCl₃): δ 1.60 (s, 6H), 3.46 (s, 3H), 3.56 (s, 2H), 7.38-7.80 (m,4H).

EXAMPLE 114-(1,1-dimethyl-2-methoxyethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR151##

A mixture of the compound prepared in Reference example 17 (165 mg, 0.62mmol), imidazole (169 mg, 2.48 mmol) and phenol (0.7 g) was heated at150 ° C for 40 min. After cooling, the reaction mixture was diluted withethyl acetate, and washed with 1N KOH and brine, and dried over MgSO₄.The filtrate was concentrated to leave a viscous oil, which was purifiedon 8 g of silica gel column eluting with 50% ethyl acetate in hexane toobtain the title compound (165 mg, 90% yield) as a colorless amorphous.

(free base)

NMR (CDCl₃): δ 1.65 (s, 6H), 3.48 (s, 3H), 3.58 (s, 2H), 6.32 (broad,1H), 7.17 (s, 1H), 7.40 (m, 1H), 7.62-7.81 (m, 3H), 7.97 (s, 1H), 8.67(s, 1H).

To a solution of the compound above (160 mg, 0.54 mmol) in methanol(2mL) was added excess HCl-methanol solution (2mL). After stirring for20 min at room temperature, the reaction mixture was concentrated.Excess HCl was evaporated with methanol (×3) to leave a white solid.Trituration with ether gave HCl salt (185 mg) as a white powder.

(HCl salt)

mp: 223°-225° C. NMR (200 MHz, DMSO-d6) δ: 9.80 (s, 1H), 8.59 (m, 1H),8.34 (m, 1H), 7.84-7.96 (m, 3H), 7.78 (m, 1H), 7.60 (m, 1H), 3.78 (s,2H), 3.29 (s, 3H), 1.57 (s, 6H). IR (KBr)ν: 1633, 1610, 1562, 1520,1474, 1397, 1108, 754 cm⁻¹.

By the same procedure as described in Reference example 17 and example11, by using corresponding amine, the compounds having the followingphysical data were given.

EXAMPLE 11 (a)6-methoxy-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR152##

(HCl salt)

mp: 169° C., (dec.) NMR (200 MHz, DMSO-d6) δ: 3.31, (s, 3H), 3.69, (t,2H), 3.92 (s, 3H), 7.50 (dd, 1H), 7.88 (s, 1H), 7.97 (s, 1H), 8.42 (s,1H), 9.21 (t, 1H), 9.99 (s, 1H). IR (KBr) ν: 3380, 3200-2700, 1636,1608, 1569, 1385, 1264, 1111, 101 8 cm⁻¹.

EXAMPLE 11 (b)6-chloro-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR153##

mp: 200°-206° C., (browning) NMR (200 MHz, DMSO-d6) δ: 10.0 (s, 1H),9.32 (m, 1H), 8.68 (s, 1H), 8.43 (s, 1H), 7.85-7.96 (m, 2H), 7.77 (d,1H), 3.90 (m, 2H), 3.66 (m, 2H), 3.32 (s, 3H). IR (KBr) ν: 1606, 1578,1555, 1524, 1498, 1445, 1395, 1354, 1320, 1108, 1012, 876, 829 cm⁻¹.

EXAMPLE 11 (c) 4-(3-ethoxypropyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR154##

mp: 170°-180° C. NMR (200 MHz, DMSO-d6)δ: 1.11 (t, 3H), 1.95 (qt, 2H),3.38-3.54 (m, 4H), 3.74 (m, 2H), 7.60 (t, 1H), 7.78 (d, 1H), 7.90 (m,2H), 8.44 (m, 2H), 9.22 (t, 1H), 9.97 (s, 1H). IR (KBr)ν:2870-3950,1624, 1556, 1473, 1400, 1311, 1090 cm⁻¹.

EXAMPLE 11 (d)6-nitro-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazolinehydrochloride ##STR155##

mp: 211° C., (dec.) NMR (200 MHz, DMSO-d6) δ: 3.33 (s, 3H), 3.66-3.71(m, 2H), 3.90-3.95 (m, 2H), 7.84 (m, 1H), 7.88 (d, 1H), 8.44 (m, 1H),8.59 (m, 1H), 9.54 (m, 1H), 9.85 (bt, 1 H), 9.94 (d, 1H). IR (KBr) ν:3430, 3220-2585, 1606, 1579, 1523, 1499, 1444, 1404, 1336, 1259, 1147,1115, 1091, 1059, 1016, 847, 825 cm⁻¹.

EXAMPLE 11(e)6-chloro-4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR156##

mp: 184°-186° C. NMR (200 MHz, DMSO-d6) δ: 3.51 (s, 4H), 3.75-3.77 (m,2H), 3.85-3.90 (m, 2H), 7.76 (d, 1H), 7.84 (m, 1H), 7.91 (dd, 1H), 8.40(t, 1H), 8.67 (m, 1H), 9.30 (bt, 1H), 9.92 (m, 1H). IR (KBr) ν:3320,3175-2825, 1602, 1574, 1497, 1439, 1398, 1343, 1118cm⁻¹.

EXAMPLE 11 (f)6,7-dimethoxy-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR157##

mp: 249°-251° C. NMR (200 MHz, DMSO-d6) δ: 3.32 (s, 3H), 3.65 (t, 2H),3.85 (m, 2H), 3.94 (s, 6H), 7.16 (s, 1H), 7.88 (s, 2H), 8.39 (s, 1H),8.92 (t, 1H), 9.95 (s, 1H). IR (KBr)ν: 3425-2365, 1642, 1603, 1573,1511, 1481, 1456, 1386, 1287, 1240, 1156, 1132, 1109, 1021, 988, 876,770cm⁻¹.

EXAMPLE 12 6-chloro-4-(2-ethoxyethyl)amino-2-(3-pyridyl)quinazoline andits salt ##STR158##

A solution of 2-(3-pyridyl)-4,6-dichloroquinazoline (1.0 g, 3.2 mmol,prepared in Reference example 5(b)) and 2-methoxyethylamine (0.53 g, 7.0mmol) in 50 mL of ethanol was heated to reflux overnight. The solutionwas concentrated, taken up in chloroform and water. After some mixing,the water layer was found to be slightly acidic and was basified withsodium carbonate. The mixture was then agitated and separated. Theorganic layer was dried over potassium carbonate and concentrated. Theconcentrate was purified on silica gel column with 5% methanol inchloroform as eluent. The product obtained was combined with additionalmaterial filtered from the aqueous layer. Obtained a total of 0.35 g(1.1 mmol) of the title compound.

(free base)

mp: 21 0°-21 2° C. NMR (200 MHz, DMSO-d6): <5 3.32 (s, 3H), 3.67 (t,2H), 3.87 (qd, 2H), 7.53 (m, 1H), 7.82 (s, 2H), 8.48 (s, 1H), 8.71 (m,3H), 9.59 (s, 1H) IR (KBr): ν 3250 (m), 1692 (s), 1535 (s), 1430 (w),1412 (w), 1366 (m), 1140 (m), 823 (m) cm⁻¹.

To a mixture of 0.35 g (1.1 mmol) of the compound prepared above in 5 mLof methanol was added 0.5 mL of 10% HCl in methanol. The solution wasconcentrated to 1 mL, triturated in ether, filtered and dried undervacuum. Obtained 0.33 g (0.85 mmol) of the hydrochloride.

(HCl salt)

mp: 190° C., (dec.) NMR (200 MHz, DMSO-d6) δ: 3.32 (s, 3H), 3.71 (t,2H), 3.94 (m, 2H), 8.01 (m, 2H), 8.12 (d, 1H), 8.75 (m, 1H), 9.01 (d,1H), 9.20 (d, 1H), 9.66 (s, 1H). IR (KBr)ν: 3425, 2500-3050, 1633, 1610,1569, 1387, 1107 cm⁻¹.

By the same procedure as described in Example 12, by using correspondingamine, the compounds having the following physical data was given.

EXAMPLE 12(a)6-chloro-4-(2-dimethylaminoethyl)amino-2-(3-pyridyl)quinazolinetrihydrochloride ##STR159##

mp =179° C. (dec.). NMR (200 MHz, D₂ O): δ 2.96 (s, 6H), 3.51 (t, 2H),4.02 (t, 2H), 7.57 (m, 1H), 7.70 (m, 3H), 8.68 (m, 2H), 9.14 (s, 1H). IR(KBr) ν: 3405, 3215, 2545, 1577, 1536, 1474, 1437, 1396, 1360, 827, 721cm⁻¹.

EXAMPLE 13 6-hydroxy-4-phenylmethylamino-2-(1-imidazolyl)quinazoline andits salt ##STR160##

To 66 mg (0.2 mmol) of the compound prepared in Example 6(g) in 1 mL ofacetic acid was added 0.8 mL (7 mmol) of 48% HBr in water. The mixturewas heated below reflux for 23 hours then heated to full reflux for fourhours. After cooling to room temperature, 15 mL of water was added tothe solution and the precipitate was filtered and dried under vacuum.The material was purified on a preparative silica gel plate with 10%methanol in chloroform. Obtained 13 mg (41 gmol) of the desired productas a solid.

(free base)

mp: 230° C., (dec.) NMR (200 MHz, CD3OD) δ: 4.86 (s, 2H), 7.05 (s, 1H),7.15-7.38 (m, 4H), 7.40-7.50 (m, 3H), 7.58-7.66 (m, 1H), 7.92 (s, 1H),8.52 (s, 1H). IR (KBr)ν: 3370, 3030, 2365, 1749, 1710, 1653, 1596, 1559,1523, 1488, 1465, 1407, 1376, 1291, 1244, 1162, 1098, 1060, 911,831cm⁻¹.

By the same procedure as described in Example 12, the hydrochloridehaving the following physical data was given.

(2HCl salt)

mp: 155° C., (dec.)

NMR (200 MHz, DMSO-d6) δ: 4.92 (m, 2H), 7.22-7.77 (m, 8H), 7.86 (s, 1H),8.38 (s, 1H), 9.36 (m, 1H), 9.94 (s, 1H). IR (KBr)ν: 3395-2640, 2365,1734, 1628, 1607, 1567, 1542, 1473, 1361, 1353, 1289, 1260, 1201, 1107,1015, 835, 753, 702 cm⁻¹.

EXAMPLE 144-(2-(2-hydroxyethoxy)ethyl)amino-6-methylsulfinyl-2-(1-imidazolyl)quinazolineand its dihydrochloride ##STR161##

To 1.38 g of the compound prepared in example 6(mm) dissolved in 10 mLof acetic acid was added 4 mL of 30% hydrogen peroxide. The reaction wasmonitored by TLC. After stirring for 1/2 hour, the mixture was pouredinto 15 g of 50% w/w sodium hydroxide and ice. The resulting mixture wasextracted four times with chloroform, dried over anhydrous magnesiumsulfate and concentrated. The concentrate was triturated in ether andcollected to obtain 1.26 g of the desired product as a white solid.

To 400 mg of the compound prepared above in 10 ml of methanol was added1 mL of 10% HCl in methanol. After ten minutes, the mixture wasconcentrated, triturated in ether and the solid collected. Obtained 441mg of the desired product as a dihyrochloride salt.

(free base)

mp: 144°-147° C. NMR (200 MHz, DMSO-d6): d 2.85(s, 3H), 3.50(m, 4H),3.70-3.90(m, 4H), 4.59(m, 1H), 7.11 (s, 1H), 7.82(m, 1H), 7.98(s, 1H),8.02(m, 1H), 8.e2(s, 1H), 8.67(m, 1H), a. 14(t, 1H).

(2HCl salt)

mp: 190°-192° C. NMR (200 MHz, DMSO-d6): d 2.89(s, 3H), 3.51(s, 4H),3.76(m, 2H), 3.89(m, 2H), 7.90(m, 2H), 8.14(m, 1H), 8.45(m, 1H), 8.89(m,1H), 9.62(t, 1H), 10.10(m, 1H).

By the same procedure as described in Example 14, by using correspondingthioether, the compounds having the following physical data were given.

EXAMPLE 14(a)4-(2-methoxyethyl)amino-6-methylsulfinyl-2-(1-imidazolyl)quinazoline andits dihydrochloride ##STR162##

(free base)

mp: 170°-173° C. NMR (200 MHz, DMSO-d6): d 2.85(s, 3H), 3.32(s, 3H),3.69(m, 2H), 3.83(m, 2H), 7.12(s, 1H), 7.77-8.10(m, 2H), 7.98(s, 1H),8.68(s, 1H), 9.16(s, 1H).

(2HCl salt)

mp: 191°-193° C. NMR (200 MHz, DMSO-d6): d 2.89(s, 3H), 3.31(s, 3H),3.67(m, 2H), 3.89(m, 2H), 7.86-8.18(m, 3H), 8.45(m, 1H), 8.89(m, 1H),9.63(t, 1H), 10.05(m, 1

EXAMPLE 14(b)6-methylsulfinyl-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride ##STR163##

mp: 167°-170° C. NMR (200 MHz, DMSO-d6): δ 2.87(s, 3H), 4.96(d, 2H),7.32-7.53(m, 5H), 7.87(d, 1H), 7.93(s, 1H), 8.15(s, 1H), 8.42(s, 1H),8.86(s, 1H),10.01(s, 1H), 10.10(t, 1H). IR (KBr): ν 3370(w), 3220(w),3060(m), 2825(m), 1617(s), 1577(s), 1541(m), 1497(w), 1444(m), 1396(s),1355(w), 1014(m), a36(w), 788(w), 702(w) cm⁻¹.

EXAMPLE 154-(2-methoxyethyl)amino-6-methylsulfonyl-2-(1-imidazolyl)quinazolinehydrochloride ##STR164##

To 0.63 g of the compound prepared in example 6(11) (free base) in 7 mLof acetic acid was added 3 ml of 30% hydrogen peroxide solution and themixture was stirred at room temperature for 17 hour. The mixture wasthen poured into a solution of 50% w/w sodium hydroxide in ice. Theresulting mixture was extracted twice with 70 mL portions of chloroform,dried over anhydrous magnesium sulfate and concentrated. The concentratewas triturated in ether and the solid collected to obtain 0.36 g of thedesired product as a white powder.

To a suspension of 300 mg of the compound above in 15 mL of methanol wasadded 1 mL of 10% HCl in methanol. The mixture become clear then aprecipitate formed. The mixture was concentrated to approximately 5 mL,diluted with ether and filtered to obtain 319 mg of the desired productas a white solid.

(free base)

mp: 241°-243° C.

(HCl salt)

mp: 226°-228° C. NMR (200 MHz, DMSO-d6): d 3.32(s, 3H), 3.36(s, 3H),3.67(m, 2H), 3.93(m, 2H), 7.81(s, 1H), 7.93(m, 1H), 8.30(m, 1H), 8.42(s,1H), 9.16(m, 1H), 9.72(t, 1H), 9.92(s, 1 H).

By the same procedure as described in Example 15, the below compoundhaving the following physical data was given.

EXAMPLE 15(a)6-methylsulfonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazolinehydrochloride ##STR165##

mp: 125°-130° C. NMR (200 MHz, DMSO-d6): δ 3.34(s, 3H), 4.97(d, 2H),7.31-7.50(m, 5H), 7.85(s, 1H), 7.93(d, 1H), 8.32(d, 1H), a.44(s, 1H),9.14(s, 1H), 9.9a(s, 1H), 10.12(t, 1H). IR (KBr): ν 3230(s), 3040(s),2705(s), 2370(m), 1616(s), 1572(s), 1524(s), 1497(m), 1399(s), 1326(s),1258(m), 1204(w), 1147(s), 1008(m), 834(w), 783(s), 730(w), 620(w),535(m) cm⁻¹.

EXAMPLE 166-hydroxymethyl-4-phenylmethylamino-2-(1-imidazolyl)quinazoline##STR166##

To a suspension of 0.68 g of the compound prepared in example 5(e) in 50mL of anhydrous tetrahydrofuran was added 2 mL of 2M lithium borohydridein tetrahydrofuran. The reaction mixture was heated at reflux for twodays. The mixture was then concentrated, diluted with water and thebasic solution was acidified with 1N hydrochloric acid. The resultingsolution was then basified with potassium carbonate, filtered and thesolid washed with water and allowed to dry. The solid material waspurified on silica gel column eluting with 5% methanol in chloroform.Obtained 85 mg of the desired product.

mp: 173° C. (dec.). NMR (200 MHz, DMSO-d6): δ 4.67(d, 1H), 4.90(d, 1H),5.47(t, 1H), 7.23(m, 1H), 7.25-7.51(m, 5H), 7.67-7.85(m, 2H), 8.12(m,1H), 8.34(m, 1H), 8.9 (s, H), 9.5 (t, H). IR (KBr): ν 3445(mw),2365(mw), 1599(s), 1559(m), 1505(mw), 1444(w), 1410(m), 1340(w),1161(w), 1073(w)cm⁻¹.

By the same procedure as described in Example 16, the below compoundshaving the following physical data were given.

EXAMPLE 16(a)4-(2-methoxyethyl)amino-6-hydroxymethyl-2-(1-imidazolyl)quinazoline##STR167##

mp: 165°-168° C. NMR (200 MHz, DMSO-d6): S 3.35(s, 3H), 3.68(t, 2H),3.80(t, 2H), 4.65(d, 2H), 5.45(t, 1H), 7.12(s, 1H), 7.68(m, 2H), 7.99(s,1H), 8.27(s, 1H), 8.62(s, 1H), 8.83(s, 1H). IR (KBr): ν 3370(m),1597(s), 1559(m), 1474(m), 1409(m) cm⁻¹.

EXAMPLE 16(b)4-[2-(2-hydroxyethoxy)ethyl]amino-6-hydroxymethyl-2-(1-imidazolyl)quinazoline##STR168##

mp: 183° C. NMR (200 MHz, DMSO-d6): δ 3.48(s, 4H), 3.76(m, 4H), 4.62(d,2H), 5.44(t, 1H), 7.10(s, 1H), 7.62-7.80(m, 2H), 7.97(s, 1H), 8.27(s,1H), 8.60(s, 1H), 8.82(bs, 1H). IR (KBr): ν 3311 (row), 3156(w),1597(s), 1558(w), 1487(w), 1438(w), 1408(ms), 1052(w) cm⁻¹.

Reference example 18 6-iodoquinazolin-2,4-dione ##STR169##

To a mixture of 25.36 g of 2-amino-5-iodobenzoic acid in 250 ml of waterand 90 mL of THF was added 7.40 g of glacial acetic acid and stirred atroom temperature. Then was added 7.82 g of potassium cyanate in waterdropwise. Left to overnight. Added another 5.47 g of potassium cyanate.Stirred overnight. A total of 160 g of NaOH pellets were addedportionwise, keeping the mixture cool in ice-water bath. The mixture wasstirred at room temperature overnight. The mixture was cooled in arefrigerator and the precipitate filtered through a sintered glassfunnel. The precipitate was then dissolved in water and acidified with4N HCl. The precipitate was collected by filtration. The solid was driedin a vacuum oven to yield 25.44 g of the title compound.

Reference example 19 6-(2-triethylsilylethylnyl)quinazolin-2,4-dione##STR170##

In a flusk was placed 0.544 g of triphenylphosphine, 0.184 g ofpalladium chloride, and 5 mL of diethylamine. Stirred under a nitrogenatmosphere. To the resulting yellow mixture was added 75 mL ofdiethylamine, followed by 10.02 g of the compound prepared in referenceexample 18. Then added 19.8 mg of cuprous iodine to the purplesuspension. Turned gray after 10 minutes. After 0.5 hr added 5.36 g oftriethylsilyl acetylene and stirred at room temperature. After 3 hrs thesolution turned purple. After another 1.5 hrs. the solution turnedbrown. Left to stir overnight. Monitored reaction by TLC. Removed thesolvent under reduced pressure at 40° C. and added water. Acidified with1N--HCl. The precipitated solid was collected by filtration, washed withwater, and dried in a vacuum oven. The solid was then passed through asilica gel column, eluting with THF. After drying yielded 10.22 g of thetitle compound having the following physical data.

NMR (200 MHz, DMSO-d6): δ 0.65(dd, 6H), 0.93(dd, 9H), 7.15(d, 1H),7.69(d, 1H), 11.38(br, 2H).

Reference example 20 2,4-dichloro-6-(2-triethylsilylethylnyl)quinazoline##STR171##

To 5.09 g of the compound prepared in reference example 19, was added 25mL of POCl₃ and warmed. Then added 1.03 g of N,N-dimethylaniline andheated to reflux. After 3.5 hrs, the excess POCl3 was removed underreduced pressure and the residue diluted in chloroform and poured slowlyover ice. The organic layer was collected and the solvent removed. Theresidue was passed through a silica gel column using 20% EtOAc/hexane asa solvent. Yielded 1.4 g of the product having the following physicaldata.

NMR (200 MHz, CDCl₃): δ 0.72(m, 6H), 1.00(m, 9H), 7.98(d, 1H), 8.33(s,1H).

Reference example 212-chloro-4-(2-methoxyethyl)amino-6-(2-triethylsilylethynyl)quinazoline##STR172##

To 1.4 g of the compound prepared in reference example 20 in 20 mL ofchloroform was added 2-methoxyethylamine and stirred at room temperaturefor 1.5 hr. Then added 4.2 ml of 1N-NaOH and heated to reflux. Left toreflux overnight. The solvent was removed under reduced pressure and theresidue taken up in chloroform and water. The organic layer wascollected and dried over anhydrous potassium carbonate. Removal ofsolvent under reduced pressure yielded 1.44 g of the title compound.

NMR (200 MHz, CDCl₃): δ 0.73 (m, 6H), 1.07(m, 9H), 3.45(s, 3H), 3.69(t,2H), 3.88(dd, 2H), 6.32(br, 1H), 7.69(d, 1H), 7.78(dd, 1H), 7.80(s, 1H).

EXAMPLE 172-(1-imidazolyl)-4-(2-methoxyethyl)amino-6-(2-triethylsilylethynyl)quinazoline##STR173##

To 1.32 g of the compound prepared in reference example 21 in 5 mL ofethanol was added excess imidazole (0.93 g) and heated in an oil bath to115° C. After 1.5 hrs. removed from heat and diluted in chloroform andwashed with 1N-NaOH, collected the organic layer and washed with water.The organic layer was extracted and dried over anhydrous potassiumcarbonate. Removal or solvent yielded 1.33 g of the title compound.

mp: 158°-160° C. NMR (200 MHz, DMSO-d6): δ 0.70(q, 6H), 1.05(t, 9H),3.30(s, 3H), 3.64(t, 2H), 3.81(dd, 2H), 7.10(s, 1H), 7.65(d, 1H),7.78(dd, 1H), 7.96(s, 1H), 8.01(s, 1H), 8.60(s, 1H), a.95(br, 1H).

By the same procedures as described in reference examples 18, 19, 20 and21, and example 17, the following compound was obtained.

EXAMPLE 17(a)2-(1-imidazolyl)-4-[2-(2-hydroxyethoxy)ethyl]amino-6-(2-triisopropylsilylethynyl)quinazoline##STR174##

mp: 155°-156° C.; NMR (200 MHz, CDCl₃): δ 1.09 (s, 3H), 1.16 (s, 18H),2.28 (br, 1H), 3.70 (m, 2H), 3.84 (dd, 4H), 3.95 (t, 2H), 6.65 (br, 1H),7.14 (s, 1H), 7.68 (d, 1H), 7.75 (dd, 1H), 7.87 (s, 1H), 7.93 (s, 1H),8.65 (s, 1H).

EXAMPLE 17(b)2-(1-imidazolyl)-4-phenylmethylamino-6-(2-triisopropylsilylethynyl)quinazoline ##STR175##

(200 MHz, DMSO-d6): δ 1.13 (s, 21H), 4.85 (s, 2H), 7.08 (m, 1H),7.21-7.40 (m, 3H), 7.46 (m, 2H), 7.65-7.82 (m, 2H), 7.93 (m, 1H), 8.55(m, 2H), 9.50 (s, 1H).

EXAMPLE 18 6-ethynyl-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazoline##STR176##

To 1.35 g of the compound prepared in example 17 in 20 mL of THF wasadded 3.3 mL of tetrabutylammonium fluoride (1M in THF). Stirred at roomtemperature for 1.5 hrs. The excess THF was removed under reducedpressure and the residue taken up in chloroform and water. The insolubleprecipitate was collected by filtration. Yielded 0.83 g of the titlecompound.

NMR (200 MHz, DMSO-d6): δ. 3.33(s, 3H), 3.66(m, 2H), 3.83(m, 2H),4.34(s, 1H), 7.11(s, 1H), 7.65(d, 1H), 7.82(dd, 1H), 7.96(s, 1H),8.57(d, 1H), 8.62(s, 1H), 8.90(broad, 1H). IR (KBr): ν 3290(s), 2945(m),1606(s), 1559(s), 1451(s), 1352(s), 1106(s), 835(s) cm⁻¹.

By the same procedure as described in example 18, the following compoundwas given.

EXAMPLE 18(a)2-(1-imidazolyl)-4-[2-(2-hydroxyethoxy)ethyl]amino-6-ethynylquinazolineand its salt ##STR177##

(free base)

mp: 166°-167° C.; NMR (200 MHz, DMSO-d6): δ 3.50 (s, 4H), 3.78 (m, 4H),4.35 (s, 1H), 4.59 (t, 1H), 7.10 (s, 1H), 7.65 (d, 1H), 7.80 (dd, 1H),7.97 (s, 1H), 8.55 (d, 1H). 8.61 (s, 1H), 8.90 (br, 1H).

(HCl salt)

mp: 178° C.; NMR (200 MHz, DMSO-d6): δ 3.51 (s, 4H), 3.74 (m, 2H), 3.87(m, 2H), 4.44 (s, 1H), 7.73 (d, 1H), 7.82 (s, 1H), 7.90 (d, 1H), 8.40(s, 1H), 8.67 (s, 1H), 9.25(br, 1H), 9.88 (s, H).

EXAMPLE 18(b) 2-(1-imidazolyl)-4-phenylmethylamino-6-ethynylquinazolinedihydrochloride ##STR178##

mp: 203°-205 ° C. NMR (200 MHz, DMSO-d6): δ 4.43(s, 1H), 4.97(d, 2H),7.33(m, 3H), 7.50(d, 2H), 7.55(d, 1H), 7.85(m, 2H), 8.40(s, 1H), 8.74(s,1H), 9.88(t, 1H), 9.97(s, 1H). IR (KBr) :v 3400, 3235, 1598, 1396, 899,842, 762, 620 cm⁻¹.

EXAMPLE 19 6-acetyl-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazoline##STR179##

To 0.541 g of the compound prepared in example 18 in 10 ml of aceticacid was added 0.7 mL of 10% H2SO₄ and 0.10 g of mercury II sulfate andheated to reflux. After 2 hours removed from heat and basified. Theyellow precipitate was filtered. The solid was washed with THF. Removedthe solvent under reduced pressure and titrated the residue in 50%ether/pentane. The solid was collected by filtration. Yielded 0.063 g ofthe desired product.

mp: 208°-210° C. NMR (200 MHz, CDCl₃): δ 2.64(s, 3H), 3.49(s, 3H),3.79(t, 2H), 3.95(q, 2H), 7.00(broad, 1H), 7.16(t, 1H), 7.74(d, 1H),7.95(t, 1H), 8.17(dd, 1H), 8.42(d, 1H), 8.67(t, 1H).

By the same procedure as described in Example 19, the below compoundhaving the following physical data was given.

EXAMPLE 19(a)4-[2-(2-hydroxyethoxy)ethyl]amino-6-acetyl-2-(1-imidazolyl)quinazoline##STR180##

mp: 164°-166° C. NMR (200 MHz, DMSO-d6): δ 2.69(s, 3H), 3.51 (s, 4H),3.76(m, 2H), 3.84(t, 2H), 4.60(br, 1H), 7.12(s, 1H), 7.73(d, 1H),7.98(s, 1H), 8.27(dd, 1H), 8.64(s, 1H), 9.00(s, 1H), 9.25(br, 1H). IR(KBr):n 3350, 1671, 1623, 1593, 1558, 1474, 1447, 1418, 1365, 1307,1270, 1111, 1051 cm⁻¹.

Formulation Example 1

The following components were admixed in conventional method and punchedout to obtain 100 tablets each containing 50 mg of active ingredient.

    ______________________________________                                        6-ethynyl-4-(2-methoxyethyl)amino-2-                                                                  5.0 g                                                 (1-imidazolyl)quinazoline                                                     cellulose calcium glycolate                                                                           0.2 g                                                 (disintegrating agent)                                                        magnesium stearate      0.1 g                                                 (lubricating agent)                                                           micro crystalline cellulose                                                                           4.7 g                                                 ______________________________________                                    

What is claimed is:
 1. A quinazoline derivative of the formula(I):##STR181## wherein R¹ is hydrogen or C1-4 alkyl; Y is single bond orC1-6 alkylene;A is(i) --CyA--(R²)_(l), (ii) --O--R⁰ or --S(O)_(p) --R⁰,in which R⁰ is R^(0A) or R^(0B) ; R^(0A) is --CyA--(R²)l; R^(0B) ishydrogen or C1-4 alkyl; p is 0-2; CyA is(1) 3-7 membered, saturated orunsaturated, monocyclic carbocyclic ring, (2) 7-membered, unsaturated orpartially saturated, monocyclic hetero ring containing as hetero atoms,one nitrogen atom, one nitrogen and one oxygen atoms, two nitrogen andone oxygen atoms, or one nitrogen and two oxygen atoms, (3) 6-membered,unsaturated or partially saturated, monocyclic hetero ring containing ashetero atoms, one nitrogen and one oxygen atoms, two nitrogen and oneoxygen atoms, or one nitrogen and two oxygen atoms, (4) 6-membered,unsaturated or partially saturated, monocyclic hetero ring containing asa hetero atom, one nitrogen atom, (5) 4- or 5-membered, unsaturated orpartially saturated, monocyclic hetero ring containing as hetero atoms,one nitrogen atom, one nitrogen and one oxygen atoms, two nitrogen andone oxygen atoms, or one nitrogen and two oxygen atoms, (6) 4-7membered, unsaturated or partially saturated, monocyclic hetero ringcontaining as hetero atoms, one or two sulfur atoms or (7) 4-7 membered,unsaturated or partially or fully saturated, monocyclic hetero ringcontaining as hetero atoms, one or two oxygen atom; R² is R^(2A) or R²B; R^(2A) is (1) --NR⁶ AR^(7A), in which R^(6A) and R^(7A) independentlyare hydrogen or C1-4 alkyl (with the proviso that R^(6A) and R^(7A) arenot hydrogen at same time), (2) --SO₂ NR⁶ R⁷, in which R⁶ and R⁷independently are hydrogen or C1-4 alkyl, (3) trifluoromethyl or (4)trifluoromethoxy; R^(2B) is (1) hydrogen, (2) C1-4 alkyl, (3) C1-4alkoxy, (4) --COOR⁵, in which R⁵ is hydrogen or C1-4 alkyl, (5) halogen,(6) nitro or (7) --NRGBR^(7B), in which R^(6B) and R^(7B) are hydrogen;Z is Z^(A) or Z^(B) ; Z^(A) is methylene, ethylene, vinylene orethynylene; Z^(B) is single bond; CyB is(1) 7-membered, unsaturated orpartially saturated, monocyclic hetero ring containing as hetero atoms,one, two or three nitrogen atoms, (2) 6-membered, unsaturated orpartially saturated, monocyclic hetero ring containing as hetero atoms,two or three nitrogen atoms, (3) 6-membered, unsaturated or partiallysaturated, monocyclic hetero ring containing as a hetero atom, onenitrogen atom, (4) 4- or 5-membered, unsaturated or partially saturated,monocyclic hetero ring containing as hetero atoms, one, two or threenitrogen atoms, or (5) 4-7 membered, unsaturated or partially saturated,monocyclic hetero ring containing as hetero atoms, one or two oxygenatoms, or one or two sulfur atoms; R³ is hydrogen, C1-4 alkyl, C1-4alkoxy, halogen or trifiuoromethyl; R⁴ is R^(4A) or R^(4B) ; R^(4A) is(1) --NHSO₂ R¹¹, in which R¹¹ is C1-4 alkyl, (2) SO₂ NR⁹ R¹⁰, in whichR⁹ is hydrogen, C1-4 alkyl or phenyl(C1-4 alkyl) and R¹⁰ is hydrogen orC1-4 alkyl, (3) --OCOR¹¹, in which R¹¹ is as hereinbefore defined, (4)hydroxy, (5) --SO₂ N═CHNR¹² R¹³ in which R¹² is hydrogen or C1-4 alkyland R¹³ is C1-4 alkyl, (6) --CONR¹⁴ R¹⁵ in which R¹⁴ is hydrogen or C1-4alkyl and R¹⁵ is C1-4 alkyl or phenyl(C1-4 alkyl), (7) ethynyl, (8)tri(C1-4 alkyl)silylethynyl or (9) acetyl; R^(4B) is (1) hydrogen, (2)C1-4 alkyl, (3) C1-4 alkoxy, (4) --COOR⁸, in which R⁸ is hydrogen orC1-4 alkyl, (5) --NR⁹ R¹⁰, in which R⁹ and R¹⁰ are as hereinbeforedefined, (6) --NHCOR¹¹, in which R¹¹ is as hereinbefore defined, (7)halogen, (8) trifluoromethyl, (9) nitro, (10) cyano, (11) C1-4alkylthio, (12) C1-4 alkylsulfinyl, (13) C1-4 alkylsulfonyl, (14)hydroxymethyl, and l, m and n independently are 1 or 2; with the provisothat(1) the group of the formula: --CyA--(R²)_(l) does not represent acyclopentyl and trifluoromethylphenyl group when Y is a single bond,that (2) a CyB ring does not bond to Z through a nitrogen atom in theCyB ring when Z is vinylene or ethynylene, that (3) a CyB ring is notpyridine or thiophene when CyA is a ring of CyA--(7) that (4) Y is not asingle bond, when A is (ii) --O--R⁰ or --S(O)_(p) --R⁰ and that (5) A isnot --CyA--(R² B)l and --OR^(0B), when Z is Z^(B) and R⁴ is R^(4B) ; orpharmaceutically acceptable acid addition salts thereof,pharmaceutically acceptable salts thereof, or hydrates thereof.
 2. Acompound according to claim 1, which is compound of the formula [I-(A)];##STR182## (wherein Z^(A) is methylene, ethylene, vinylene orethynylene.
 3. A compound according to claim 1, which is compound of theformula [I(B)]; ##STR183## (wherein Z^(B) is single bond; R^(4A) is--NHSO₂ R¹¹, SO₂ NR⁹ R¹⁰, --OCOR¹¹, hydroxy, --SO₂ N═CHNR¹² R¹³,--CONR¹⁴ R¹⁵, ethynyl, tri(C1-4 alkyl)silylethynyl or acetyl.
 4. Acompound according to claim 1, which is compound of the formula [I-(C)];##STR184## (wherein Z^(B) is single bond; A^(C) is --CyA--(R² A)l,--O--R^(0A) or --S(O)p--R⁰ ; R^(0A) is --CyA--(R²)l; R⁰ is hydrogen,C1-4 alkyl or--CyA--(R²)l; p is 0-2; R^(2A) is --NRGAR^(7A) (with theproviso that R^(6A) and R^(7A) are not hydrogen at same time), --SO₂ NR⁶R⁷, trifluoromethyl or trifluoromethoxy; R^(4B) is hydrogen, C1-4 alkyl,C1-4 alkoxy, --COOR⁸, --NR⁹ R¹⁰, --NHCOR¹¹, halogen, trifluoromethyl,nitro, cyano, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl,hydroxymethyl.
 5. A compound according to claim 1, wherein CyB is7-membered, unsaturated or partially saturated, monocyclic hetero ringcontaining as hetero atoms, one, two or three nitrogen atoms.
 6. Acompound according to claim 1, wherein CyB is 6-membered, unsaturated orpartially saturated, monocyclic hetero ring containing as hetero atoms,two or three nitrogen atoms.
 7. A compound according to claim 1, whereinCyB is 6-membered, unsaturated or partially saturated, monocyclic heteroring containing as hetero atoms, one nitrogen atom.
 8. A compoundaccording to claim 1, wherein CyB is 4- or 5-membered, unsaturated orpartially saturated, monocyclic hetero ring containing as hetero atoms,one, two or three nitrogen atoms.
 9. A compound according to claim 1,wherein CyB is 4-7 membered, unsaturated or partially saturated,monocyclic hetero ring containing as hetero atoms, one or two oxygenatoms, or one or two sulfur atoms.
 10. A compound according to claim 1,wherein CyB is pyridine ring.
 11. A compound according to claim 1,wherein CyB is imidazole ring.
 12. A compound according to claim 1,wherein CyB is triazole or pyrrole ring.
 13. A compound according toclaim 1, wherein CyB is furan or thiophene ring.
 14. A compoundaccording to claim 1, wherein A is OH, --O--C1-4 alkyl, --S(O)p--H,or--S(O)p--C1-4 alkyl.
 15. A compound according to claim 1, wherein A is--CyA--(R²)l, --O--CyA--(R²)l or--S(O)p--CyA--(R²)l.
 16. A compoundaccording to claim 1, wherein Y is single bond.
 17. A compound accordingto claim 1, wherein Y is methylene or ethylene.
 18. A compound accordingto claim 1, wherein Z is single bond.
 19. A compound according to claim1, wherein Z is methylene.
 20. A compound according to claim 2, whichis:4-phenylmethylamino-2-((1-imidazolyl)methyl)quinazoline,4-phenylmethylamino-2-((1-imidazolyl)methyl)quinazoline,6-chloro-4-phenylmethylamino-2-(1-imidazolylmethyl)quinazoline,6-chloro-4-phenylamino-2-(1-imidazolylmethyl)quinazoline,6-chloro-4-(3-carboxyphenyl)amino-2-(1-imidazolylmethyl)quinazoline or4-phenylmethylamino-2-(2-(3-pyridyl)vinyl)quinazoline,andpharmaceutically acceptable acid addition salts thereof,pharmaceutically acceptable salts thereof, or hydrates thereof.
 21. Acompound according to claim 3, whichis:6-dimethylaminosulfonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazoline,6-dimethylaminomethylideneaminosulfonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazoline,6-(phenylmethylaminosulfonyl)-4-phenylmethylamino-2-(1-imidazolyl)quinazoline,6-phenylmethylaminocarbonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazoline6-ethylaminocarbonyl-4-phenylmethylamino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinazoline,6-hydroxy-4-phenylmethylamino-2-(1-imidazolyl)quinazoline, 6-(1-imidazolyl)-4-(2-methoxyethyl)amino-6-(2-triethylsilylethynyl)quinazoline,6-ethynyl-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazoline,6-(1-imidazolyl)-4-phenylmethylamino-6-ethynylquinazoline or6-acetyl-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazoline,andpharmaceutically acceptable acid addition salts thereof,pharmaceutically acceptable salts thereof, or hydrates thereof.
 22. Acompound according to claim 4, whichis:4-(2-methylthioethyl)amino-6-methoxy-2-(1-imidazolyl)quinazoline,4-(2-methylsulfinylethyl)amino-6-methoxy-2-(1-imidazolyl)quinazoline,4-(2-methylsulfonylethyl)amino-6-methoxy-2-(1-imidazolyl)quinazoline,4-(3-trifluoromethylphenylmethyl)amino-2-(3-pyridyl)quinazoline,4-(4-(N,N-dimethylamino)phenylmethyl)amino-2-(3-pyridyl)quinazoline,4-(4-sulfamoylphenylmethyl)amino-2-(3-pyridyl)quinazoline,4-(4-trifuloromethoxyphenylmethyl)amino-2-(1-imidazolyl)quinazoline,4-(3-trifluoromethoxyphenylmethyl)amino-2-(1-imidazolyl)quinazoline,4-(2-phenoxyethyl)amino-6-methoxy-2-(1-imidazolyl)quinazoline or4-(2-phenoxyethyl)amino-2-(1-imidazolyl)quinazoline,and pharmaceuticallyacceptable acid addition salts thereof, pharmaceutically acceptablesalts thereof, or hydrates thereof.
 23. A pharmaceutical composition forthe treatment of mammals, which comprises, as active ingredient, aneffective amount of a compound of the formula (I), ##STR185## wherein Y,A, Z, CyB , R¹, R³, R⁴, m and n are as defined in claim1,pharmaceutically acceptable acid addition salts thereof,pharmaceutically acceptable salts thereof, or hydrates thereof and apharmaceutically acceptable carrier.
 24. A method for the treatment ofmammals, to prevent or treat at least one disease selected from thegroup consisting of hypertension, heart failure, myocardial infarction,angina, atherosclerosis, cardiac edema, renal insufficiency, nephroticedema, hepatic edema, asthma, bronchitis, dementia, immunodeficiency andpulmonary hypertension which method comprises administering to a patientan effective amount of a compound of the formula (I) ##STR186## whereinY, A, Z, CyB , R¹, R³, R⁴, m and n are as defined in claim1,pharmaceutically acceptable acid addition salts thereof,pharmaceutically acceptable salts thereof, or hydrates thereof.
 25. Thecomposition of claim 23 wherein the mammals are humans.
 26. The methodof claim 24 wherein the mammals are humans.